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

LHRH can improve a disease-free phase and a moderate survival (if it’s combined with primary radiation),
reducing circulating testosterone levels to so-called castrate levels (< 0.5 ng/mL). Anti-androgen therapy
is part of the common hormone therapy that is used with drugs which can stop the action of particular
hormones. Presently, the anti-androgen therapy is always combined with orchiectomy or with LHRH
agonists as a first-line hormone therapy, referred as combined androgen blockade (CAB). During the first
days of treatment with LHRH analogues there could be an overload of testosterone: to counteract this event,
specific LHRH’s antagonists have been proposed .
[43]
At the first symptoms of metastasis, in CRPC patients, the cytotoxic chemotherapy is usually initiated .
[44]
Although cancer cells still express ARs, at some point they no longer respond to ADT, and prostate cancer
become recurrent . It has been discovered that there are some AR mutations often expressed in hormone-
[45]
refractory prostate cancer and these mutations cause a deregulation of transcriptional activity. These events
are in contrast with the purpose of targeted therapies designed specifically to inhibit the receptor functions .
[46]
Eventually, it has been studied that prostate cancer cells can resist to ADT, surviving and developing an
androgen independence in different ways, such as stimulating growth factor pathways, activating stress-
dependent survival genes, increasing cytoprotective chaperone networks, and escaping from apoptosis
processes [47-49] .

The regulatory effects of androgens on prostate cancer cells are still debated; in particular, the effects of
modulation of the autophagy process during androgen deprivation have been investigated . Previously, it
[50]
was observed that autophagy was induced if androgen-sensitive LNCaP cells were cultured in the absence of
serum; otherwise, if dihydrotestosterone was introduced, the autophagic process was reduced. This suggests
that specific androgenic hormones produce a down regulation of autophagy process . In addition, two
[51]
independent studies have shown that cell death increases if LNCaP cells undergo androgen deprivation,
suggesting that autophagic might exert a protection role toward prostate cancer cells [51,52] .

THE DIFFERENT EFFECTS OF AUTOPHAGY MODULATION IN PRECLINICAL MODELS OF
PROSTATE CANCER CELLS
The autophagy process
Autophagy is a homeostatic process whereby cellular components are engulfed into vesicles known as
autophagosomes, which then fuse with lysosomes and are consequently subjected to proteolytic degradation .
[53]
In 1963 the Nobel Laurate, Christian de Duve, introduced the concept of autophagy , now this definition
[54]
has been assigned to several intracellular processes, including micro- and macro-autophagy, chaperone-
mediated autophagy, and all of them eventually converge towards a common degradation phase mediated
by lysosomes [55,56] .

Macro-autophagy, generally referred to as autophagy, has been experimentally proven to be involved in the
pathogenesis of different diseases including cancer .
[57]

At a molecular level, the kinase mTOR is a critical regulator of autophagy induction, with activated mTOR
(MAPK and Akt signaling) it suppresses autophagy, whereas a negative regulation of mTOR, p53 and
AMP-activated protein kinase (AMPK) signaling, promotes it. Three related serine/threonine kinases,
UNC-51-like kinase -1, -2, and -3 (i.e. ULK1, ULK2 and UKL3) act downstream of the mTOR complex.
ULK1 and ULK2 form a large complex with the mammalian homolog of an autophagy related gene product
(mAtg13) and the scaffold protein FIP200. Class III phosphoinositide 3 kinase (PI3K) complex, containing
hVps34, Beclin-1, p150, and Atg14-like protein or ultraviolet irradiation resistance-associated gene product
(UVRAG), is required for the induction of autophagy. Autophagosome formation in controlled by Atg
genes proteins through Atg12-Atg5 and LC3-II complexes. Atg12 is conjugated to Atg5 in an ubiquitin-like