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4 Prostate Cancer, Apoptosis, Autophagy and Ferroptosis: Cell Death Mechanisms…
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“apoptosome,” cytochrome c binds to and activates procaspase-9 and Apaf-1
[121, 122].
When procaspase-9 clumps together in this way, caspase-9 gets activated. It has
been found that Smac/DIABLO and HtrA2/Omi can enhance apoptosis by blocking
the activity of inhibitors of apoptosis proteins (IAP) [123, 124]. Several other mitochondrial proteins have been found to bind to IAP and inhibit its activity; however,
results from gene knockout studies raise doubts about whether or not this is sufcient proof to classify a mitochondrial protein as “pro-apoptotic” [125]. Although
Apoptosis-Inducing Factor (AIF), endonuclease G, and Caspase-Activated DNase
(CAD) are the second set of pro-apoptotic proteins produced from mitochondria
during apoptosis, this process happens after the cell has already decided to die.
When AIF moves into the nucleus, it causes the DNA to be broken up into around
50–300kb pairs and the nuclear chromatin surrounding the nucleus to condense
[126]. The term for this initial step of nuclear condensation is “stage I condensation” [127]. Furthermore, endonuclease G gets into the nucleus and splits nuclear
chromatin into oligonucleosomal DNA pieces [128]. There is no caspase requirement for the activity of AIF or endonuclease G.Further release from mitochondria
causes CAD to translocate to the nucleus, where it causes oligonucleosomal DNA
breakage and progressive chromatin condensation after caspase-3 cleavage [129].
What happens later on is known as “stage II” condensation, and it is much more
noticeable than stage I condensation [127].
These apoptotic mitochondrial processes are regulated and controlled by proteins belonging to the Bcl-2 family [130]. Despite the importance of the tumor suppressor protein p53in regulating the Bcl-2 family of proteins, the precise processes
by which it does this remain unclear [131]. The Bcl-2 family of proteins governs
mitochondrial membrane permeability and can be either pro-apoptotic or antiapoptotic. It is noteworthy that a total of 25 genes have been identied in the Bcl-2
family. Some of the anti-apoptotic proteins include Bcl-2, Bcl-x, Bcl-XL, Bcl-XS,
Bcl-w, BAG, and some of the pro-apoptotic proteins include Bcl-10, BCL2Associated X Protein (Bax), Bak, Bid, Bad, Bim, Bik, and Blk. These proteins have
special signicance since they can determine if the cell commits to apoptosis or
aborts the process. It is thought that the main mechanism of action of the Bcl-2 family of proteins is the regulation of cytochrome c release from the mitochondria via
alteration of mitochondrial membrane permeability.
A few possible mechanisms have been studied but none have been proven denitively. Mitochondrial damage in the Fas pathway of apoptosis is mediated by the
caspase-8 cleavage of Bid [132, 133]. This is one example of the “cross-talk”
between the death receptor (extrinsic) pathway and the mitochondrial (intrinsic)
pathway [104]. Serine phosphorylation of Bad is associated with 14-3-3, a member
of a family of multifunctional phosphoserine binding molecules. When Bad is phosphorylated, it is trapped by 14-3-3 and sequestered in the cytosol but once Bad is
unphosphorylated, it will translocate to the mitochondria to release cytochrome
c [134].
Bad can also heterodimerize with Bcl-Xl or Bcl-2, neutralizing their protective
effect and promoting cell death [135]. The process by which Bcl-2 and Bcl-Xl,
when Bad is not present, prevent mitochondrial cytochrome c release is unclear.
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More research has demonstrated that Bcl-2 and Bcl-XL mainly regulate caspase
protease activation to prevent apoptotic death [20]. An additional protein designated
“Aven” appears to bind both Bcl-Xl and Apaf-1, thereby preventing activation of
procaspase-9 [20]. There is evidence that overexpression of either Bcl-2 or Bcl-Xl
will down-regulate the other, indicating a reciprocal regulation between these two
proteins.
The Bcl2 family includes the pro-apoptotic proteins Puma and Noxa. In
p53-mediated apoptosis, Puma is a key player. In vitro studies demonstrated that
Puma overexpression is associated with BAX overexpression, BAX conformational
change, mitochondrial translocation, cytochrome c release, and decreased mitochondrial membrane potential [136]. Noxa is also a candidate mediator of p53induced apoptosis. Studies show that this protein can localize to the mitochondria
and interact with anti-apoptotic Bcl-2 family members, resulting in the activation of
caspase-9 [137]. Since both Puma and Noxa are induced by p53, they might mediate
the apoptosis that is elicited by geno-toxic damage or oncogene activation. The Myc
oncoprotein has also been reported to potentiate apoptosis through both p53dependent and -independent mechanisms [138].
4.4.2 Extrinsic Pathway
Apoptosis initiation pathways involving extrinsic signaling entail connections
mediated by transmembrane receptors. Part of the tumor necrosis factor (TNF)
receptor gene superfamily, these include death receptors [139]. In addition to having
cyteine-rich extracellular domains, TNF receptors also share a “death domain” in
their cytoplasm that is around 80 amino acids long [140]. An absolutely essential
function of this death domain is to relay the death signal from the surface of the cell
to the signaling pathways within the cell. The most well-studied ligands and death
receptors so far are FasL/FasR, TNF-α/TNFR1, Apo3L/DR3, Apo2L/DR4, and
Apo2L/DR5 [140–143].
To fully understand the extrinsic phase of apoptosis, one should use the FasL/
FasR and TNF-α/TNFR1 models. Receptor clustering and binding to homologous
trimeric ligands are features of these models. To connect with receptors, ligands
trigger the recruitment of cytoplasmic adapter proteins, which include death
domains. Adherence of Fas ligand to Fas receptor initiates the binding of the adapter
protein Fas-Associated Death Domain Protein (FADD) [144, 145]. Similarly, when
TNF ligand binds to TNF receptor, the binding of the adapter protein TNF ReceptorAssociated Death Domain (TRADD) with recruitment of FADD and RIP follows.
Dimerization of the death effector domain is the next step for FADD to bind with
procaspase-8. A death-inducing signaling complex (DISC) is created at this moment,
which causes procaspase-8 to be auto-catalytically activated [146]. Moreover, activation of caspase-8 initiates the nal stage of cell death. By attaching to FADD and
caspase-8, a protein known as c-FLIP can suppress death receptor-mediated apoptosis [147, 148]. An additional possible regulator of cell death is a protein named
4 Prostate Cancer, Apoptosis, Autophagy and Ferroptosis: Cell Death Mechanisms…
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Toso. This protein has been demonstrated to prevent T cell death caused by Fas by
inhibiting caspase-8 processing [149].
4.4.3 Perforin/Granzyme Pathway
In T-cell mediated cytotoxicity, antigen-bearing cells are killed by sensitized CD8+
cells, a kind of type IV hypersensitivity. Through the FasL/FasR connection, cytotoxic T lymphocytes (CTLs) trigger apoptosis, which allows them to destroy target
cells via the extrinsic pathway [150]. On the other hand, there is a new way for them
to kill tumor cells and cells infected with viruses. This involves secreting the molecule perforin, which forms transmembrane pores, and then exophytically releasing
cytoplasmic granules into the cell of interest [151]. Granzyme A and granzyme B,
two serine proteases, are the granules’ most crucial components.
It should be mentioned that granzyme B can activate procaspase-10 and cleave
factors like ICAD (Inhibitor of Caspase Activated DNAse) by cleaving proteins at
aspartate residues [152]. There have been reports indicating that granzyme B can
enhance the death signal through the mitochondrial route, namely by cleaving Bid
and inducing the release of cytochrome c [153, 154]. On the other hand, granzyme
B can activate caspase-3 directly. This initiates the execution phase of apoptosis
directly, skipping the upstream signaling cascades.
Granzyme B-induced death is thought to rely on the mitochondrial pathway as
well as the direct activation of caspase-3 [155]. In order to regulate the proliferation
of type 2 helper T (Th2) cells, new research shows that this granzyme B cytotoxicity
technique is essential [156]. Furthermore, since inhibiting the ligands of death
receptors and caspases does not affect apoptosis, the results show that these pathways are unrelated to the T cell receptor-induced death of activated Th2 cells.
Contrarily, granzyme B does not inuence apoptosis or the regulation of cytotoxic
type 1 helper cells; nonetheless, Fas-Fas ligand interaction, adaptor proteins with
death domains, and caspases are all involved.
Granzyme A activates caspase-independent pathways and plays a crucial role in
cytotoxic T cell mediated apoptosis. When granzyme A reaches a cell, it triggers
DNA nicking through the tumor suppressor gene product DNAse NM23-H1 [23].
By inducing tumor cell death, this DNAse plays a crucial function in immunological surveillance for cancer prevention. The NM23-H1 gene is generally inhibited by
the nucleosome assembly protein SET.Protease granzyme A breaks down the SET
complex, which releases NM23-H1 inhibition and causes DNA to be degraded in an
apoptotic manner. Not only does the SET complex suppress NM23-H1, but it also
plays a crucial role in DNA repair and chromatin shape. It appears that the proteins
SET, Ape1, pp32, and HMG2 collaborate to safeguard DNA and chromatin structure (23). Hence, granzyme A’s inactivation of this complex likely adds to apoptosis
by preventing the integrity of DNA and chromatin structure from being maintained.
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4.5 Apoptosis inProstate Cancer
When it comes to cancer-related deaths among American men, prostate cancer is
second only due to lung cancer [157, 158]. More importantly, it is also the most
often diagnosed cancer in this demographic. Androgen ablation therapy is effective
in reducing the size of most prostate cancers since it removes the hormone that the
tumor cells use to grow [159]. Regrettably, hormone ablation causes prostate cancer
to develop to androgen-independent illness, which is resistant to hormone ablation
and other systemic chemotherapies [160]. Radiosensitivity in prostate cancer is
inuenced by apoptosis, which seems to be the main mechanism by which tumor
cells die off in response to androgen ablation and chemotherapeutic drugs [159,
160]. The development of treatment resistance in advanced prostate cancer is caused
by the acquisition of anti-apoptotic signal transduction.
Prostate cancer, like other cancers, is thought to progress by the interplay of cell
growth, proliferation, and apoptotic components. Interactions like these, issues with
apoptosis regulation, cause prostate cancer cells to differentiate, avoid apoptosis,
and proliferate indenitely [161]. Research including a large number of clinical factors and biochemical markers is necessary to determine the effective apoptotic
mechanisms in the advancement of prostate cancer [162, 163].
With regard to prostate cancer, there are two mechanisms for apoptosis: the
intrinsic and the extrinsic. The extrinsic pathway is activated by death receptors and
involves caspase-8, which in turn activates caspase-3 to produce apoptosis. Bcl family anti-apoptotic regulators can block the intrinsic pathway’s cytochrome c release,
which activates caspase-9. Apoptosis is triggered by the activation of caspase-3, the
last step. Important dietary regulators in this apoptotic pathway include bioactive
chemicals like avones [163].
Moreover, malignant prostate cancer results from a mutated gene. Some examples of these alterations include changes in biosynthesis and amplication, such as
point mutations in the ligand-binding domain (LBD) of AR or AR overexpression
[164]. Furthermore, the apoptotic pathway of prostate cancer is inhibited by mutations in the RNase L gene, which is an inherited allele of prostate cancer type 1
(HPC1) [165].
In reaction to various cellular stressors, including DNA or free radical damage,
the tumor suppressor gene p53, which is most often linked with cell death, controls
cell-cycle progression and cell death. P53 can trigger apoptosis by mitochondrial
overexpression of BAX; however, this mutation of P53 prevents apoptosis, allowing
cancer cells to multiply endlessly [158, 166]. As metastatic illness or hormoneindependent tumors advance, p53 mutations in prostate cancer become increasingly
common, although they are rare in the early, well-differentiated stage [167].
In addition, proteins belonging to the Bcl-2 family impact mitochondrial activity; these proteins include both pro- and anti-apoptotic molecules [168]. The outer
mitochondrial membrane is a stable anchor for several members of the Bcl-2 family
due to a hydrophobic region of amino acids close to their carboxyl-terminus. Bid,
Bim, and Bad are members of the Bcl-2 family that target mitochondria but do not
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have these membrane anchoring domains. Members that prevent cell death, such as
Bcl-2 and Bcl-xL, prevent mitochondrial apoptosis by blocking the release of cytochrome c. Bax, Bad, and Bid are proapototic Bcl-2 family members that inhibit their
activity, which in turn triggers the release of cytochrome c from mitochondria and
the activation of caspase cascades [168]. Tumor cell survival is regulated by the
relative abundance of pro- and anti-apoptotic family members.
Research has shown that aggressive prostate cancer morphologies are characterized by a large upregulation of Bcl-2 and other members of its family, which inhibit
cell death [169, 170]. More research has represented that prostate cancer and other
cancers can develop resistance to radiation and chemotherapy when Bcl-2 and
Bcl-xL are overexpressed. In addition, the androgen-signaling axis in prostate cancer cells relies on the Bcl-2 family [170]. Moreover, Coffey and colleagues demonstrated that androgens suppress the expression of pro-apoptotic Bcl-2 family
members such as Bax in cells that are susceptible to androgens in prostate cancer
[171]. More investigations, in this eld, has revealed that there is evidence that
prostate cancer cells can survive in androgen-free environments due to increased
Bcl-2 and Bcl-xL expression [169, 172]. This suggests that Bcl-2/Bcl-xL overexpression is important for both the function and prediction of androgen-independent
recurrences in prolonged androgen ablation therapy [170]. While it is true that Bcl-2
family expression alterations can lead to treatment resistance, it is equally important
to recognize and explain the dynamic cross-talk between this “powerful” family and
other anti-apoptotic pathways affected by external ligand-receptor communication.
Furthermore, an extremely conserved tumor suppressor gene, Phosphatase and
tensin homolog deleted on chromosome 10 (PTEN) regulates the P13K/AKT signal
transduction pathway, leading to cellular death. The activation and targeting of
AKT’s numerous downstream effectors are dependent on its phosphorylation,
which PTEN blocks [173]. Apoptotic resistance and constitutive activation of the
P13K/AKT pathway are outcomes of PTEN loss, which is prevalent in treatmentresistant and poorly differentiated prostate tumors [174]. By restoring PTEN activity in PTEN decient prostate cancer cell lines, researchers were able to enhance
their susceptibility to caspase-8-mediated apoptosis and facilitate BH3 Interacting
Domain Death Agonist (BIDD) breakage, which led to the release of cytochrome c
and mitochondrial-driven apoptosis [175]. Second messengers activate AKTs
through phosphatidylinositol 3′-kinases (P13Ks). On the other hand, PTEN phosphatases work to counteract this phosphorylation [176]. Plasmid negativity in prostate cancer can lead to constitutive AKT phosphorylation, whereas tumors positive
for PTEN can experience autocrine and paracrine cell membrane receptor-ligand
interactions that stimulate and upregulate AKT [177]. Phosphorylated AKT appears
to suppress cellular apoptosis in prostate cancer due to the strong interaction
between this effector and various other anti- apoptotic pathways. It has been demonstrated that activated AKT activates MDM2, which in turn causes p53 proteolysis
and the suppression of p53 mediated apoptosis, while simultaneously stimulating
cell-cycle progression [176, 178]. In addition to releasing Bcl-2 and inhibiting mitochondrial apoptosis, activated AKT inactivates Bad and caspase-9 [173, 176, 179].
In addition, phosphorylation of IκB occurs as a result of upregulated P13K/AKT
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activity, which in turn permits the nuclear translocation of NF-κB and the consequent inhibition of apoptosis caused by NF-κB [173, 176]. Inhibition of androgendeprivation-induced apoptosis can result from phosphorylated AKT inducing AR
phosphorylation and upregulating AR expression [179, 180].
The hallmarks of aggressive prostate cancer include both PTEN inactivation and
AKT phosphorylation, according to a growing body of recent ndings. On the other
hand, xenograft models produced from metastatic prostate cancer cell lines show a
loss of PTEN in 60% of cases, while only 10–15% of original prostate malignancies
had PTEN inactivation [173, 177]. In addition, a Gleason score more than 6 and
aggressive local disease (T3b-T4 tumors) have been linked to PTEN depletion
[181]. Independent prognostic indicators and markers for aggressive illness include
AKT phosphorylation. Only benign tissues, not prostate cancer, are linked to high
levels of AKT phosphorylation [182]. In poorly differentiated tumors (Gleason
8–10), nearly 90% of tissues tested exhibit a substantial level of phosphorylated
AKT [183], and AKT phosphorylation correlates with Gleason score [184].
Recurrence was indicated by higher AKT phosphorylation in prostate cancer specimens with Gleason scores of 5–6, a group of patients whose prognosis is notoriously difcult to predict [184]. Furthermore, it was recently determined that AKT
phosphorylation, rather than mitotic index or Gleason score, was a better predictive
indication of recurrence [185]. The advancement of resistant prostate cancer following long-term androgen ablation therapy has been linked to the loss of PTEN and
phosphorylation of AKT, which is not surprising given their associations with chemotherapy resistance [175, 179]. Experimental evidence suggests that new targeting
techniques that restore PTEN activity or suppress AKT phosphorylation might
induce signicant cell death and make cancer cells more sensitive to chemotherapy,
both in laboratory settings and using xenograft models [175, 179].
One emerging class of medications that may make prostate cancer treatment
more challenging is apoptosis inhibitors. The IAPs are a kind of caspase inhibitors
that decrease cell death by directly inhibiting caspases 3, 7, and 9 [123]. As of this
writing, eight human IAPs have been the subject of substantial research: survivin,
X-linked inhibitor of apoptosis protein (XIAP), IAP1, and IAP2 [186]. It has been
suggested in reference that there might be a positive feedback loop involving the
two pathways, even if they can all decrease effector caspases, since IAP1 and IAP2
can upregulate NF-κB expression [187]. Evidence from animal studies and patient
specimens taken after prostatectomy suggests that these four IAPs are overexpressed during the early stages of prostate cancer [186]. Numerous tumor models
have demonstrated that IAPs can suppress apoptosis in response to various chemotherapeutic drugs [188], but the role of IAPs in treatment resistance in prostate
cancer is a topic of “active” research that has only just begun to emerge. It has been
found that inhibiting XIAP increases chemotherapy sensitivity in prostate cancer
cell lines that are normally resistant to the treatment [189]. It has been suggested
that IAPs may play a role in androgen independence, according to another small
research of 23 patients who underwent neoadjuvant androgen ablation, wherein the
expression of IAP1 and IAP2 was signicantly increased [187]. More and more
evidence is pointing to IAPs as a cause of treatment resistance in prostate cancer. By
4 Prostate Cancer, Apoptosis, Autophagy and Ferroptosis: Cell Death Mechanisms…
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manipulating IAP pathways, we may be able to bypass the apoptotic resistance in
intracellular apoptotic escape mechanisms like AKT and Bcl-2.
Moreover, Survivin, XIAP, c-IAP1, and c-IAP2 levels were decreased in PC-3
and DU145 prostate cancer cells treated with apigenin. The apoptotic cascades
involved an increase in cytochrome c (5, 10, 20, 40μM), a decrease in Bcl-xL and
Bcl-2, and a peak in BAX [190]. In addition, at doses of 1, 5, 10, and 20μM, LNCaP
cells showed an increase in the expression of the cancer suppressor protein p21
[191]. At 2.5, 5, 10, and 20μM concentrations, it was observed that IκB Kinase α
(IKK α) was inhibited in PC-3 and 22Rv1 cells, and that p65 activation was suppressed as well [192]. The activation of NF-κB by IKK α regulates inammation
and the advancement of cancer. Additionally, research has demonstrated that apigenin can cause extrinsic apoptosis in PC-3 cells and prostate cancer stem cell
(CSC) (CD44+) isolated from there at a concentration of 25μM by increasing the
production of caspase-8, -3, and TNF-a [193].
Twenty weeks of oral administration of apigenin at doses of 20 or 50μg/mouse/
day (wt/vol) was carried out on male Transgenic Adenocarcinoma of the Mouse
Prostate (TRAMP) mice that were 8 weeks old. Hence, the PI3K/AKT/FOXO pathway was able to suppress the growth of prostate cancer without causing any harm or
weight loss [194]. Doses like these are consistent with what humans have been
shown to consume on a regular basis in avonoid studies [195]. After injecting PC-3
and 22Rv1 cells subcutaneously into the anks of mice, researchers found that giving the same dose of apigenin orally slowed tumor growth, reduced tumor growth
via blocking IKK phosphorylation, and induced cell death. Using two different
amounts of apigenin did not seem to have any negative consequences in this mouse
model [192].
With a molecular weight of 284.26g/mol and a chemical formula of C16H12O5,
acetin is a 5,7-dihydroxy-4′-methoxyavone [196]. Plants belonging to the
Asteraceae family, as well as safower and propolis, are the primary sources of
acetin [197]. Levels of phospho-AKT and phospho-GSK-3β were decreased in
DU145 prostate cancer cells treated with acacetin, whereas levels of the cancer suppressor p53 were increased (12.5 and 5μM, respectively). In addition, apoptosis
was caused by a decrease in XIAP and Bcl-2 levels, and the activation of phosphoIκB and NFκB was hindered [196].
By lowering STAT3 phosphorylation in DU145 cells, acacetin (20, 30, and
50μM) reduces cancer cell proliferation and growth. It then induces apoptosis by
inhibiting the expression of STAT3 target proteins, including Bcl-2, Bcl-xL, Mcl-1,
cyclin D1, with survivin among them. Direct binding by interacting with the SH-2
domain of numerous signaling proteins, including the Src (steroid receptor coactivator) tumor protein of STAT3, was another mechanism by which acetin demonstrated anticancer action [198].
In LNCaP and DU145 cells, Acacetin (25, 50, 100μM) inhibited cell growth and
caused a cell-cycle arrest in the G1 or G2-M phase as a result of an increase in Ciap/
p21 and a decrease in CDK2, CDK4, and CDK6. G2-M phase arrest was more pronounced in LNCaP cells compared to DU145 cells because Cdc25C, Cdc2/p34, and
cyclin B1 were reduced to greater extents in the former. Closure of
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poly-(ADP-ribose) polymerase (PARP) also contributed to cell death [199]. The
possibility of toxicity due to cytochrome P450 inhibition was documented by Zhou
etal. in their study of rats given 50mg/kg of acacetin intraperitoneally. Nevertheless,
the particular toxicity has not been reported as of yet. Therefore, additional studies
are necessary [200].
4.6 Ferroptosis Machinery
In order for cells to produce glutathione, System X
−
, an antiporter that does not rely
c
on sodium, exports internal glutamate and imports extracellular cystine across the
membrane in a ratio of 1:1 [201, 202]. The two components that make it up are
SLC7A11 and SLC3A2. The conserved site cys158 of SLC7A11 and cys109 of
SLC3A2 form a disulde link that connects the two proteins [203]. Another subtype
of CD44, CD44v, interacts with and stabilizes SLC7A11 on cancer cell surfaces
[204]. SLC7A11 is an integral part of system X
−
and is a multichannel transmem-
c
brane protein. The molecular chaperone responsible for ensuring the stability and
correct localization of the SLC7A11 protein is SLC3A2, a single transmembrane
protein [203]. To enhance ferroptosis, new small compounds like erastin and
sorafenib have been discovered as inhibitors of system X
−
[205, 206]. One of the
c
many environmental pollutants is the poisonous metal cadmium, or Cd. Consumption
of tainted food and drink, along with inhalation and smoking, are the main routes of
Cd exposure. Some epidemiological studies, like those conducted by the International
Cancer Society, have linked Cd to an increased risk of prostate cancer [207].
Moreover, Zhang and colleagues have illustrated that prolonged exposure to cadmium impeded ferroptosis and enhanced prostate cancer cell proliferation.
Cd-induced prostate cancer metastasized, and RNA sequencing showed that
lncRNA OIP5-AS1 was upregulated in a considerable way. Through the miR- 128-3p/
SLC7A11 axis, OIP5-AS1 suppresses ferroptosis [208]. Inhibiting tumor growth is
one of the key functions of the tumor suppressor gene p53 [209]. Inhibiting cystine
uptake by reducing SLC7A11 expression and making cells more susceptible to ferroptosis, p53 is involved in ferroptosis, according to recent studies [210] To stop
castration-resistant prostate cancer (CRPC) from spreading, ubendazole promotes
ferroptosis, downregulates glutathione peroxidase 4 (GPX4), and inhibits SLC7A11
expression through p53 induction. Furthermore, when it came to treating colorectal
cancer, ubendazole and 5-uorouracil (5-FU) worked together in a synergistic
fashion. It enhances the pharmacological efcacy and induces ferroptosis by reducing SLC7A11 expression after concurrent use [211].
Protecting cells and membranes from peroxidation, the antioxidant enzyme
GPX4 employs glutathione as a cofactor to ward against lipid peroxidation. By
alternating between its reduced (GSH) and oxidized (GSSG) forms, glutathione is
able to take part in redox biological reactions [212]. In order to make prostate cancer cells more sensitive to docetaxel, ChaC1, an enzyme that is specic for glutathione, can reduce the amount of GSH within the cells. When GPX4 is not functioning
4 Prostate Cancer, Apoptosis, Autophagy and Ferroptosis: Cell Death Mechanisms…
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properly, it can cause lipid peroxidation and the buildup of reactive oxygen species
(ROS), which can then lead to ferroptosis [213]. On top of that, GPX4 can convert
harmful lipid peroxides (like R-OOH) into their corresponding alcohols (like
R-OH). To render GPX4 inactive, RSL3 binds to selenocysteine in the enzyme’s
active site [214]. One of the main inhibitors of ferroptosis is GPX4. Researchers and
cancer patients alike have found serum miRNA to be an exciting new target in the
ght against the disease. Alterations to regulatory components in cellular physiological processes are brought about by microRNAs, which primarily interact with
the ‘3’-UTR of target mRNAs and either cause their destruction or block their translation. Prostate cancer patients exhibited a decrease in miR-15a expression. Negative
regulation of GPX4 expression can occur when miR-15a interacts with the
3′-untranslated region (UTR) of GPX4 messenger RNA.One way to increase cell
death in prostate cancer is to utilize a miR-15a mimic or siGPX4 [215]. Cells from
more advanced prostate cancers express SLC7A11 and GPX4 at high levels. One
way to enhance cancer cell death is by inducing ferroptosis with the ferroptosis
activator erastin or RSL3. When ferroptosis activator is used alongside secondgeneration anti-androgen medications such enzalutamide or abiraterone, the conventional treatment for advanced prostate cancer can further suppress tumor
development [216]. Figure4.3 highlights the ferroptosis mechanism.
Typically, reactive oxygen species (ROS) include free radicals, peroxides, and
superoxide [217]. They are normal metabolites made in live cells; as unstable compounds, they are important for signal transduction and tissue homeostasis [218].
Metabolism, inammation, neurogenesis, and carcinogenesis are just a few of the
physiological and pathological processes that ROS are engaged in [219, 220].
Damage to DNA, lipids, and proteins occurs as a result of oxidative stress, which in
turn causes cells to release dangerous levels of reactive oxygen species (ROS) [221].
The most notable aspect of ferroptosis is the high levels of polyunsaturated fatty
acids (PUFA) in the cell membrane, which makes it extremely susceptible to damage from reactive oxygen species (ROS). Cancer cells are more susceptible to ferroptosis and ROS buildup than normal ones. An anticancer medication that is
commonly used is cisplatin. Cisplatin resistance is a major problem for prostate
cancer patients undergoing chemotherapy. By increasing ROS production, exacerbating cell-cycle arrest, and cisplatin-induced apoptosis, the ferroptosis activator
RSL3 makes prostate cancer cells more sensitive to the drug [222]. As allicin breaks
down, one of its primary active components is diallyl trisulde, or Dopamine
Transporter (DAT). According to research, DAT has many biological functions,
including anti-tumor, bacteriostasis, oxidative stress, and involvement in inammatory response modulation. It suppresses cancer cell proliferation in prostate cancer
by increasing reactive oxygen species, which in turn induces ferritin breakdown
and, ultimately, ferroptosis [223]. It was in 1971 when Tu youyou initially isolated
artemisinin from Artemisia annua [224]. An antimalarial action is imparted by this
semiterpene lactone. Research in recent years has shown that it induces ferroptosis
and has anticancer effects. There was no discernible impact of artemisinin on PC3
and LNCaP cell lines, while it was found to cause ferroptosis in prostate cancer cell
DU145 [225]. One of artemisinin’s active metabolites is dihydroartemisinin, or
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M. Hashemi et al.
Fig. 4.3 The mechanism of ferroptosis (Biorender.com)
Docosahexaenoic Acid (DHA).Several cancer cells, including those in the lung and
brain, have been found to be cytotoxic to DHA, according to a plethora of studies
[226, 227]. It has the ability to decrease cancer cell proliferation, activate autophagy
and ferroptosis in cancer cells. Current study does not establish its involvement in
prostate cancer ferroptosis; nonetheless, this could be an area for future investigation. The active ingredients in traditional Chinese medicine often work in tandem
with one another or in addition to one another. By controlling ADAMTS18, ROS,
Nrf2, GPX4, and other molecules to regulate ferroptosis, traditional Chinese medicine (TCM) has the properties of many targets and can regulate a range of signal
pathways, in contrast to specic medications. Research into inducing ferroptosis in
prostate cancer cells using traditional Chinese medicine could be a promising avenue for future investigation.
Several biological processes rely on iron as a cofactor [228]. Iron excess causes
lipid peroxidation and deadly reactive oxygen species (ROS) generation [229]. The
transmembrane glycoprotein known as transferrin receptor 1 (TFR1) is in charge of
importing iron, which is stored and delivered as an iron-protein complex, primarily
ferritin [230]. An enzyme titled iron oxide reductase steam3 (STEAP3) converts
ferric ions from Fe3+ to Fe2+ [231]. At last, the endosome, which is mediated by