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Gabriele et al. J Cancer Metastasis Treat 2018;4:17  I  http://dx.doi.org/10.20517/2394-4722.2018.06                         Page 3 of 17

               stimulated protein synthesis; moreover, these cells also have an inefficient autophagy process due to reduced
               catabolism . The inhibition of glycolysis by the promoting some kind of metabolic stresses may be used to
                        [22]
               improve therapies. A novel therapeutic paradigm was the treatment introduced by DiPaola et al. , using
                                                                                                  [23]
               2-Deoxy-D-glucose (2DG), an inhibitor of glycolysis and a glucose analogue that blocks the uptake of glucose
               and induced cytotoxicity and autophagy in different prostate cancer cells. It was, therefore, hypothesized
               that prostate cancer is metabolically fragile because of dependence on glycolysis and impaired autophagy.

               Interestingly, altered lipid metabolism has also been demonstrated by multiple groups to play an important
               role in prostate cancer progression . Fatty acid synthase (FAS), a rate-limiting enzyme in de novo lipogenesis,
                                           [24]
               is frequently over-expressed in prostate cancers [25,26] . Correspondingly, pharmacological or molecular
               inhibition of either FAS or other lipogenic enzymes, like acetyl-coenzyme A carboxylase (ACC) and ATP
               citrate lyase (ACL), suppressed both in vitro and in vivo tumor growth [27,28] . FASs are also stimulated by
               androgen hormones as seen in LNCaP cell accumulation of lipid droplets (LDs) within the cytoplasm
                                                                                                        [29]
               containing both triacylglycerols (TGs) and cholesterols, which are enveloped by a monolayer of phospholipids
               and associated proteins . LDs can be metabolized by hormone-regulated cytosolic lipases that break down
                                   [30]
               the TGs into fatty acids which are then utilized for β-oxidation , but there is a second pathway involving
                                                                     [31]
               lipolysis mediated by autophagy. Recently, Singh et al.  reported that in rat hepatocytes, autophagosomes
                                                             [32]
               sequestered LDs and caused lysosomal lipolysis. An alternative pathway of lipolysis has been observed
               also in prostate cancer cells, further explaining how prostate cancer cells may adapt to survive in hostile
               environmental conditions . Although androgens promote prostate cancer cell growth in part by increasing
                                     [33]
               the expression of several of these lipogenic enzymes [24,34,35] , it is not known whether androgens may promote
               the formation of these lipid reservoirs by additional mechanisms that may also be critical for tumorigenesis .
                                                                                                        [36]
               Statins (or HMG-CoA reductase inhibitors) are a class of drugs used to lower cholesterol levels by inhibiting
               the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver.
               Statins such as atorvastatin (ATO), in addition to their effects on cholesterol biosynthesis, have attracted
               considerable interest for their possible utility in cancer prevention and therapy . It has been demonstrated
                                                                                  [37]
               by in vitro studies that autophagy and autophagy-associated cell death in PC3 prostate cancer cells can
               be induced by ATO . Clinically, lowering of serum cholesterol is the first effect of statin treatment; even
                                [38]
               though the inhibition of prostate cancer cell growth could seem independent from the lowering of serum
               cholesterol, both can be mediated by effects on the mevalonate pathway. Recently, it has been discovered
               that ATO inhibited the synthesis of geranylgeranyl pyrophosphate (i.e. an intermediate in the HMG-CoA
               reductase pathway used by organisms in the biosynthesis of terpenes and terpenoid), played an important
               role in the induction of autophagy and suppressing prostate cancer cell growth . Specifically, the authors
                                                                                   [39]
               found a stress-responsive miRNA, called miR-182, which mediates the activity of ATO in prostate cancer
               cells.

               A landscape of ADT in prostate cancer
               In patients with advanced prostate cancer, ADT remains the most effective standard treatment, inducing
               programmed cell death and inhibiting cell proliferation . Unfortunately, after short term remissions, cancer
                                                             [40]
               cells may escape from this treatment, survive and develop androgen-independent growing capabilities by
               several mechanisms . Surviving tumor cells shows a phenotype known as Castration-resistant prostate
                                [41]
               cancer (CRPC) and death usually occurs within 3 years in the majority of patients . The principal
                                                                                           [42]
               androgens produced in the testes are testosterone and the more active metabolite dihydrotestosterone.
               Androgens work after binding and trans-activating androgen receptor (AR), which regulates gene expression
               by interacting with different co-regulators during prostate cancer progression. The down-regulation of the
               levels of androgens, or preventing their entrance into prostate cancer cells, can reduce the tumor growth. To
               date, there are many hormone therapy protocols to achieve this goal. ADT is now performed with surgical
               castration (bilateral orchiectomy) or with luteinizing hormone-releasing hormone (LHRH) agonist therapy.
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