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4 Prostate Cancer, Apoptosis, Autophagy and Ferroptosis: Cell Death Mechanisms…
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divalent metal transporter 1 (DMT1), releases Fe2+ into the cytoplasm’s unstable
iron pool [232]. Iron acts as a crucial component in the production of reactive oxygen species (ROS) through enzymatic and non-enzymatic processes, which in turn
makes cells more susceptible to ferroptosis. In a specic investigation, Bordini and
colleagues exhibited that oxidative damage can be used by high-dose iron to suppress the proliferation of prostate cancer cells. Iron had a synergistic impact with
bicalutamide in cells that were resistant to the drug [233]. A great deal of research
in the last several years has concentrated on ferroptosis inducers and how they work.
4.7 Ferroptosis inProstate Cancer
Numerous human disorders have been linked to ferroptosis, including neurodegeneration, ischemia-reperfusion injury, and malignancies (including prostate cancer)
[201, 234–236]. When compared to normal cells, tumor cells rely on iron more for
their rapid growth. Iron addiction is the name given to this condition [231]. A new
light on the origins and progression of tumor disorders has been shed by the revelation of ferroptosis. Ferroptosis inhibits tumor growth, according to mounting data.
An anticancer method that involves the use of inducers to induce ferroptosis or alter
genes associated to ferroptosis is being considered. Consequently, learning about
ferroptosis and how it works in prostate cancer research is crucial.
New research has identied the phosphatase and tensin homolog (PTEN) gene as
a tumor suppressor located on chromosome 10. Its nal product, the PTEN protein,
can phosphorylate both lipids and proteins. By inhibiting the PI3K/AKT signaling
pathway, PTEN primarily blocks the anti-tumor impact of PI3K by acting on its
downstream target molecule, PIP3 [237]. Encoding numerous genes for important
enzymes in the adipogenesis pathway (including SCD, FASN, and ACLY), sterol
regulatory element-binding protein 1 (SREBP1) is a critical transcription factor that
controls lipid metabolism. Researchers discovered that the PI3K/AKT/mTOR pathway, which inhibits ferroptosis, is activated when the PTEN gene is defective or
when PI3K is activated, promoting SREBP1/SCD mediated adipogenesis. An
emerging strategy for prostate cancer treatment could involve blocking mTOR [238].
In vivo and invitro research shown that knocking down these two genes enhances
ferroptosis [239]. The genes AIFM2 and NFSI were identied in a prostate cancer
gene risk model as being involved in ferroptosis. Additionally, prostate cancer is
associated with elevated levels of pannexin2 (PANX2). By preventing the proliferation of prostate cancer cells, this gene knockout enhances ferroptosis [240]. It is
intriguing to note that ferroptosis-related genes have emerged as possible therapeutic targets and prognostic indicators in prostate cancer patients, thanks to the discovery of database mining. The androgen receptor (AR) and its splice variants continue
to be the primary drivers of castration-resistant prostate cancer (CRPC) progression,
which is dependent on the ongoing activation of androgens for cell growth in prostate cancer. As a traditional ferroptosis inducer, erastin has the ability to block the
AR and its splice variants’ transcriptional activity both in test tubes and living
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M. Hashemi et al.
organisms. Furthermore, it was discovered that the growth inhibitory impact of
docetaxel was improved when administered in combination with erastin to treat
CRPC.With minimal toxicity and adverse effects, erastin can further increase the
anticancer effect of docetaxel in invivo tests, and it causes no visible damage to
numerous organs of mice [241]. Additionally, Li etal. discovered that ferroptosis
activator RSL3in conjunction with anti-androgens slowed the proliferation of prostate cancer cells in xenografts from mice [216]. In the future, additional clinical
trials can be carried out to establish the signicance of ferroptosis in the management of prostate cancer. Gene analysis for AR inhibitor resistance led to the discovery of 2,4-Dienoyl-CoA reductase (DECR1). One gene that AR negatively regulates
is DECR1. Ferroptosis is enhanced in CRPC cells when this gene is deleted [242].
Recent research has shown that antagonists of AR that contain isothiocyanate (ITC)
can reduce AR and its spliceosome levels. Lipid peroxidation and ferroptosis are
enhanced in prostate cancer cells when BSO, a GSH inhibitor, is combined with it
[243]. Based on the research conducted by Kumar etal., which shown that supraphysiological testosterone can hinder tumor proliferation through the production of
lipid peroxides, one potential therapeutic approach could involve targeting the lipid
metabolism associated with prostate cancer cells in order to halt their growth [244].
In another investigation Fu and collaborators revealed that in prostate cancer
cells, luteolin promotes TFEB nuclear translocation and increases ferritinophagy,
leading to ferroptosis [245]. Following treatment with 60μM luteolin, RWPE-1 did
not alter signicantly at 12, 24, and 48h. Nevertheless, DU145 and PC-3 cells were
found to be signicantly different. Luteolin promoted the demise of PCa cells.
Lutein administration resulted in an increase of AnV-PI-positive dead cells and a
decrease of cell viability and Ki67 expression. Fer-1, Nec-1, 3-MA, and Z-VADFMK were able to counteract the effects of luteolin on the viability, proliferation,
and AnV-PI-positive dead cells of DU145 and PC-3 cells. The two most effective
were Fer-1 and 3-MA.Autophagy and ferroptosis were enhanced in DU145 and
PC-3 cells when exposed to luteolin. Additionally, DU145 and PC-3 cells experienced enhanced autophagy due to luteolin, which facilitated ferroptosis.
Nevertheless, luteolin’s capacity to stimulate ferritin lysosome degradation was
reversed upon TFEB knockdown. Luteinolytic induction by luteolin also enhanced
PCa ferroptosis invivo.
A key component of ferroptosis is the endoplasmic reticulum stress response, as
has been shown in recent research. Cancer cells can decrease ferroptosis and contribute to drug resistance generation by activating the endoplasmic reticulum stress
pathway, on the one hand. Endoplasmic reticulum stress, in contrast, may play a
role in the co-regulation of ferroptosis and apoptosis and can enhance cell ferroptosis [246]. Research has also demonstrated that ferroptosis inducers can activate the
ERK-eIF2 pathway through the ATFα-ATF4-CHOP stress cascade in the endoplasmic reticulum, even though they do not cause apoptosis. The expression of ATF6 is
greater in LNCaP-AI cells compared to LNCap-A cells. The tolerance to ferroptosis
4 Prostate Cancer, Apoptosis, Autophagy and Ferroptosis: Cell Death Mechanisms…
97
is mediated by the highly expressed ATF6 through the transcriptional activation of
PLA2G4A, and the effect of enzalutamide on CRPC xenograft growth is enhanced
when Ceapin-A7 inhibits ATF6α signaling [247]. It is crucial to comprehend the
connection between ferroptosis and ER stress, apoptosis, and autophagy in order to
conquer cancer cells’ resistance to drugs. However, this subeld of prostate cancer
has received surprisingly little attention from researchers. Additional investigation
on the possibility of such reciprocal control in prostate cancer is warranted.
Moreover, Zou and colleagues demonstrated that Polyphyllin I activates the
ERK/DNMT1/ACSL4 axis, leading to ferroptosis in castration-resistant prostate
cancer cells [248]. PPI slowed the growth of CRPC cells, decreased GSH and GPX4
levels, and increased Malondialdehyde (MDA), Fe2+, and ROS levels; however, an
Extracellular Signal-Regulated Kinase (ERK) inhibitor undid PPI’s effect on ferroptosis. Inhibiting DNMT1 was the mechanism by which PPI reduced the ACSL4
promoter methylation level. DNMT1 downregulation enhanced CRPC cell ferroptosis through regulation of ACSL4. In naked mice, PPI inhibited the development of
CRPC and caused ferroptosis. One potential novel approach to treating CRPC is the
use of PPI, which can trigger ferroptosis in CRPC cells through the ERK/DNMT1/
ACSL4 axis.
4.8 Conclusion andRemarks
In multicellular creatures, homeostasis and the selective death of dangerous or diseased cells are both maintained by active or programmed cell death. Thus, catastrophic diseases like cancer and autoimmune disorders (too little cell death) and
degenerative diseases (too much cell death) can occur when the signaling pathways
that cause cell death are not properly regulated. Therefore, it is reasonable to assume
that the development of multicellular creatures is the rationale behind the presence
of effective and well-regulated methods to cause cell death. It may seem paradoxical, though, that there must be so many distinct mechanisms for death signaling.
When seen as a whole, cell death induction is best understood as a straightforward
signaling pathway leading to a single effect: cell death. Nonetheless, nearby cells
and, at occasion, the entire organism are affected by the manner in which a cell dies.
The inammatory characteristics and immunological responses elicited by apoptotic and necrotic cells, for instance, are distinct. Furthermore, specic death programs involve the secretion of signals that stimulate the growth of adjacent tissues
in order to compensate for the loss of their own. The signals may vary depending on
the kind of cell death. Lastly, there is a denite interconnection between the routes
that indicate death.
Conict of Interest The authors declare no conict of interest.
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