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Page 8 of 17 Gabriele et al. J Cancer Metastasis Treat 2018;4:17 I http://dx.doi.org/10.20517/2394-4722.2018.06

A recent work by Scherz-Shouval et al. showed that elevated levels of reacting oxygen species (ROS)
[100]
activate autophagy. In addition, it was highlighted that androgen-mediated ROS generation promoted
prostate cancer cell growth , which provided the rationale that androgenic regulation of autophagy
[101]
required a specific ROS signal. This evidence was recently further confirmed, reporting that elevated ROS
levels contributed to the androgen-induced autophagy, to intracellular lipid accumulation, and finally to
tumor cell growth . Overall, it is clear that the regulation of ROS levels within the cells is critical: although
[36]
too much ROS can trigger apoptosis, moderate levels promote cell signaling activities that are needed for
both proliferation and survival .
[102]

Autophagy and apoptosis crosstalk in prostate cancer
It is known that autophagy is particularly important as a survival mechanism in tumors with defects in the
apoptotic pathway, supporting an already suggested therapeutic paradigm of a dual apoptotic and autophagic
inhibition . Prostate cancer cells could be sensitized to different apoptotic stimuli by inhibiting autophagy,
[103]
which happens during ADT. In fact, appropriate stimuli can lead prostate cancer cells to apoptosis,
even though these cells tend to evolve into an androgen-resistant phenotype . To this regard, a recent
[104]
investigation by Saleem et al. demonstrated that employing the well-established Bcl-2 inhibitor, ABT-737,
[105]
in combination with chloroquine resulted in enhanced cytotoxicity in prostate cancer in vitro and in vivo.
These results also highlighted the importance in clinical studies for the evaluation of the crosstalk pathways
between apoptosis and autophagy . Tumor necrosis factor-alpha (TNF-α) and TNF-related apoptosis-
[100]
inducing ligand (TRAIL), members of the death receptor ligand superfamily, as apoptotic markers, have been
suggested as potential anti-prostate cancer pharmacological targets [106,107] . In the LNCap cells the apoptotic
response was enhanced by inhibiting pharmacological autophagy. Furthermore, the apoptotic cytotoxicity
induced by TRAIL, in prostate cancer cell lines, was effectively increased by blocking autophagy by siRNAs
targeting autophagic genes such as BECN1 or ATG7 .
[108]

Shin et al. reported that docosahexaenoic acid (DHA), an omega-3 fatty acid present in cold-water fatty
[109]
fishes, leads to mitochondrial ROS generation and reduces phospho-mTOR and phospho-Akt expression
levels in concentration-dependent manner in p53-mutant DU145 and PC3 cells. These results suggest that
DHA may be beneficial for patients with p53-mutant prostate cancer and show its possible use in clinical
therapies .
[109]
Many natural compounds are studied for their antitumor features. Recently, the effects of Marchantin M
(Mar), a naturally occurring macrocyclicbisbibenzyls, have been tested, which resulted in a favorable apoptosis
modulation . Through this observation, it was hypothesized that caspase-independent mechanisms can
[110]
also contribute to its cytotoxic effect on prostate cancer cells. Very recently, Jiang et al. revealed that
[111]
the Mar-induced cell death was additionally associated with the activation of autophagy, together with the
induction of ER stress and the inhibition of proteasome activity. These results enforced the goal of the
identification of chemotherapeutic compounds able to trigger apoptotic as well as autophagic cell death in
prostate cancer cells, for a successful application in cancer therapy.

Novel molecular actors for autophagy tuning in prostate cancer models
Recent contributions highlighted tyrosine kinases (TKs) and histone deacetylase (HDAC) inhibitors as
promising modulators of autophagy activity in novel therapeutic schemes in prostate cancer models . It was
[112]
reported that TKs play a key role in tumor sensitivity to radiation and chemical-induced apoptosis . Non-
[113]
receptor tyrosine kinases (NRTK) are shown to participate in processes such as cell proliferation and migration
in prostate cancer. There are several NRTK families, classified based on their structural similarities, that might
potentially interfere with cell death balance in prostate cancer [23-25] . In particular, it has been shown that the
administration of autophagy interfering molecules or drugs sensitized these cells toward Src tyrosine kinase
inhibitor-based therapies . Specifically, AR is phosphorylated by Src kinase complex, resulting in AR nuclear
[114]