Abstract
The prolyl isomerase Pin1 expression level is reportedly increased in most malignant tissues and correlates with poor outcomes. On the other hand, acetyl CoA carboxylase 1 (ACC1), the rate limiting enzyme of lipogenesis is also abundantly expressed in cancer cells, to satisfy the demand for the fatty acids (FAs) needed for rapid cell proliferation. We found Pin1 expression levels to correlate positively with ACC1 levels in human prostate cancers, and we focused on the relationship between Pin1 and ACC1. Notably, it was demonstrated that Pin1 associates with ACC1 but not with acetyl CoA carboxylase 2 (ACC2) in the overexpression system as well as endogenously in the prostate cancer cell line DU145. This association is mediated by the WW domain in the Pin1 and C-terminal domains of ACC1. Interestingly, Pin1 deficiency or treatment with Pin1 siRNA or the inhibitor juglone markedly reduced ACC1 protein expression without affecting its mRNA level, while Pin1 overexpression increased the ACC1 protein level. In addition, chloroquine treatment restored the levels of ACC1 protein reduced by Pin1 siRNA treatment, indicating that Pin1 suppressed ACC1 degradation through the lysosomal pathway. In brief, we have concluded that Pin1 leads to the stabilization of and increases in ACC1. Therefore, it is likely that the growth-enhancing effect of Pin1 in cancer cells is mediated at least partially by the stabilization of ACC1 protein, corresponding to the well-known potential of Pin1 inhibitors as anti-cancer drugs.
Highlights
The morbidity of cancers is increasing, and development of novel therapies is eagerly awaited
Among many lipid metabolism enzymes, acetyl CoA carboxylase 1 (ACC1), which converts from acetyl CoA to malonyl CoA is one of the rate limiting enzymes involved in lipogenic processes [9]
ACC1 knockdown by siRNA significantly suppressed the proliferation of both cell lines (Figure 1B), indicating that disruption of the fatty acids (FAs) supply suppresses cancer cell proliferation
Summary
The morbidity of cancers is increasing, and development of novel therapies is eagerly awaited. Cancer cells have various distinguishing features contributing to their high proliferation rates, which could serve as a target for novel therapies [1]. From the perspective of metabolism, most cancer cells exhibit a marked increase in glycolysis and suppression of the oxidative phosphorylation needed to produce ATP, a phenomenon www.oncotarget.com known as the Warburg effect [2,3]. The underlying molecular mechanism has not yet been fully elucidated, it reportedly involves increased expression of prolyl isomerase Pin which regulates both pyruvate kinase M2 and phosphoglycerate kinase 1 in cancer cells [4,5]. Increased production of malonyl CoA leads to suppression of carnitine palmitoyl transferase activity which is a rate limiting enzyme of FA oxidation [10]. The inhibition of FA synthesis using inhibitors or genetic manipulations reportedly suppresses the growth of various cancers including prostate, ovarian and breast tumors [14,15,16,17,18]
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