Page 12 - Read Online

Gabriele et al. J Cancer Metastasis Treat 2018;4:17 I http://dx.doi.org/10.20517/2394-4722.2018.06 Page 7 of 17

cells to apoptosis in a serum-free medium, but not in cells in medium with serum or dihydrotestosterone.
This suggest that autophagy process during androgen deprivation can protect LNCap cells from death. In
other cancer cell lines it has been demonstrated that autophagy is modulated by growth factors contained in
serum through activating the mTOR pathway .
[75]
Cell death, in certain androgen deprivation situations under in vitro condition on epithelial prostate cancer
cells, can arise by blocking autophagy processes via interfering with genetic or pharmacology means.

Furthermore, it has been observed that there is a parallelism between autophagy stimulation by androgen-
ablation in prostate cancer cells and autophagy induction in some breast cancer cells during anti-hormone
therapy. It was hypothesized that breast cancer cells tend to increase autophagy levels to develop a resistance to
anti-estrogens . To this regard, chloroquine induce cell death in LNCaP cells in a time and dose-dependent
[88]
way, combined with an androgen deprivation . At the same time, efficacy of androgen-ablation cell death can
[89]
be enhanced by a combination of pharmacological inhibition of autophagy and chemotherapy . Additional
[90]
drugs that potentially are known to interfere with autophagy flux include bafilomycin A1, 3-methyladenine
and pepstatin A . However, these pharmacological molecules produces many off-target effects in different
[91]
cellular pathways .
[91]
At this moment there are not enough in vivo studies on the combination of androgen deprivation and
autophagy inhibition, but the in vitro results obtained to date show the potentiality of the combination of
conventional ADT and autophagy-modulation in prostate cancer patients .
[50]

Autophagy and androgen receptor interplay
In regulation of prostate development as well as in carcinogenesis, AR is a critical transcription factor, but
in the autophagy process, the role of AR remains poorly understood . In fact, in PC3 AR-negative cells,
[92]
statin is an autophagy inducer, but not in LNCaP AR-positive cells . In contrast, in LNCaP cells autophagy
[93]
process is inhibited by dihydrotestosterone treatment, but this does not happen in PC3 cells . In addition,
[51]
other studies showed that cell death may increase, under androgen deprivation by inhibiting autophagy
process in LNCaP cells and suggesting a role of autophagy as a protector of prostate cancer cells [93,94] . Due
to these contrasting results, in prostate cancer cell, the role of androgen/AR signals in altering autophagy
remains unclear . Traditional androgen deprivation therapy to treat prostate cancer may not reverse the
[95]
AR regulated autophagy pathway because this pathway was found under different conditions at different
androgen concentrations. In particular, Jiang et al. have used the compound ASC-J9 to specifically degrade
[95]
AR in AR-positive cells.

Results revealed increased autophagy and decreased cell growth compared to those of sham-treated AR-
positive cells. Therefore, targeting AR to promote autophagy may represent a new potential therapeutic
approach to prostate cancer .
[39]
It is emerging that different mechanisms regulate the autophagy process in androgen-ablation conditions .
[96]
In case of hypoxic conditions, autophagy can be induced by different independent pathways including
the inhibition of mTOR kinase and hypoxia-inducible factors (HIF-1). Another mechanism that activate
an autophagic response is controlled by energetic stress . In particular, androgen deprivation may cause
[94]
the genesis of autophagic vesicles which incorporate LD. The catabolism of lipids, known as lipophagy,
represents a way to support energy demand and helps in the surviving of cells during ADT . The loss of
[25]
energy production leads to an activation of AMPK which, again, leads to suppression of mTOR signaling;
this events cause fatty acid oxidation, glycolysis and, lastly, autophagy . It is very interesting that about
[97]
[98]
40% human prostate cancers have an over-expression of AMPK, which confirms its activation in different
metabolic pathways .
[99]