Page 9 - Read Online
P. 9

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
   4   5   6   7   8   9   10   11   12   13   14