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Page 6 of 17 Gabriele et al. J Cancer Metastasis Treat 2018;4:17 I http://dx.doi.org/10.20517/2394-4722.2018.06

models ; on the contrary, other prostate cancer cell lines, such as PC3 and DU-145, were quite resistant to
[71]
the treatment. Recently, Lamoureux et al. showed that AZD5363 induced cell death in the drug-resistant
[72]
prostate cell lines by means of a chloroquine-mediated autophagy inactivation.
Chloroquine is known as a drug for the treatment of rheumatoid arthritis and malaria and to achieve an
anti-HIV activity . Chloroquine may be a clinically effective drug in prostate cancer, due to its ability
[73]
to block lysosome acidification, preventing fusion with autophagosomes and, therefore, inhibiting the
autophagy process . Currently, many clinical trials used chloroquine to increase the effects of different
[74]
targeted therapies such as bortezomib, temsirolimus, or gemcitabine in various cancers . Early antitumor
[75]
activities have been demonstrated in some of these trials. Furthermore, some studies evidenced that breast
cancer cells could be sensitized to cisplatin by chloroquine, in an autophagy inhibition-independent manner,
irrespective to Atg12 or Beclin-1 expression . Previous studies reported that cell death in breast cancer
[76]
[77]
and in glioma cells is increased by the combination of chloroquine (or other lysosomotropic agents) and
[78]
PI3K pathway inhibitors. It was demonstrated that in vitro administration of D,L-sulforaphane (SFN), a
synthetic racemic analogue of broccoli constituent L-sulforaphane, can inactivate histone deacetylase 6,
therefore, interfering with the expression of androgen receptor genes in prostate cancer cells . However,
[79]
SNF also induced a cytoprotective autophagy in cultured human prostate cancer cells and it can be further
enhanced with the pharmacologic inhibition of autophagy using chloroquine. The combined treatment was
associated with decreased cell proliferation, increased apoptosis, alterations in protein levels of autophagy
regulators Atg5 and phospho-mTOR, and suppression of biochemical features of epithelial-mesenchymal
transition .
[80]

Pyruvate kinase isoenzyme type M2 (PKM2), a modulator of glycolysis, also regulates the autophagy process
by up-regulating LC3B or Beclin-1 in glioma cells or in cancer-associated fibroblasts [81,82] . Since Sp-1 directly
regulates PKM2, Ling et al. (2017) have recently found that a specific microRNA, miR-361-5p, inhibits
[15]
CRPC cell proliferation, metabolism, and autophagy by directly targeting Sp1/PKM2 signaling, which is a
potential target in PCa therapy.

Recently, it has been reported that the retinoic acid receptor responder (RARRES1)/tazarotene-induced gene-1
(TIG-1), a novel retinoid inducible gene first identified in skin raft cultures, modulates a series of signaling
pathways inducing autophagy and inhibiting angiogenesis. The over-expression of RARRES1 can lead to
the block of MAPK, to the increase of Beclin-1, Atg3, LC3-II protein expression, and finally, the inhibition
of mTOR expression . These studies strongly indicated the attractive prospect of blocking autophagy
[83]
processes combined with targeted therapy as a promising therapeutic approach for prostate cancer .
[72]
Zeng et al. (2018) have very recently investigated the role of a prostate leucine zipper protein (PrLZ) in
[84]
combination with docetaxel-(the first-line standard approach in PCa) resistance in PCa, focusing on PrLZ-
regulating autophagy pathway. PCa cells are protected from docetaxel induced-apoptosis by overexpression
of PrLZ. The negative regulation of autophagy by PrLZ is mediated through LKB1/AMPK signaling pathway.
The autophagy pathway and PrLZ can become a good therapeutic target for CRPC and, especially, docetaxel-
resistant CRPC therapy . Autophagy has, generally, a protective function on cancer cells so maybe, if
[84]
autophagy is properly inhibited, it could be a clinical strategy to contrast therapeutic resistance in prostate
cancer, when is associated with partial failure of radiation or chemotherapeutic schemes . On the contrary,
[85]
in androgen-independent prostate cancer cells, it has been shown that autophagy induction may sensitize
cells to radiation . Despite these contrasting results, a therapeutic benefit for prostate cancer patients can
[86]
come from either induction or inhibition of autophagy, depending on the specific tumor environment, and
ultimately, to the adopted therapeutic scheme . Radiation therapy is a cytoprotective autophagy inducer
[49]
in prostate cancer cells , it was also reported that incubation of LNCaP cells in serum-free medium lead
[87]
to a pro-death autophagy process . Li et al. found out that the inhibition of autophagy can lead LNCaP
[67]
[51]