Glyoxalase 2 Is Involved in Human Prostate Cancer Progression as Part of a Mechanism Driven By PTEN/PI3K/AKT/mTOR Signaling With Involvement of PKM2 and ERα

Abstract

Targeting glyoxalases metabolic pathway may represent a strategy to selectively inhibit advanced PCa. Prostate 77:196-210, 2017. © 2016 Wiley Periodicals, Inc.

Glyoxalases in Urological Malignancies

“…Notably, a distinctly high activity of Glo1 was observed in 22 out of 22 PCa specimens and none to little activity in 10 out of 10 non-malignant specimens. Although preliminary, these results opened new pathways of investigation towards the study of Glo1 expression, either at mRNA, protein or functional level, in PCa tissues and normal counterparts or in differently aggressive and invasive PCas [36,37,[52][53][54][55]. Overall, these studies strongly indicated Glo1 as a novel important protein involved in PCa genesis and progression, thus suggesting an oncogenic role for this enzyme in this neoplasm.…”

“…Overexpression of Glo1 in PCa cells would aim at maintaining low intracellular levels of the glycolysis-derived cytotoxic metabolite MG, as a survival defense strategy. Indeed, in vitro studies performed with PCa cell lines, causatively demonstrated this role [24,25,36], in addition to pointing out a pro-survival function for this protein by eluding apoptosis in a mechanism involving the desensitization of NF-kB pathway [25]. Only one study, based on the proteomic analysis of normal and malignant prostate tissues, identified Glo1 among the proteins lost in PCa [56].…”

“…Differently from Glo1, the role of Glo2 in PCa has been scarcely investigated [36,37,49,50]. Ayoub et al [49] and Di Ilio et al [50] first attempted to evaluate Glo2 enzymatic activity in human PCa cell lines and tissues.…”

“…Nevertheless, RCC recurs in 20-40% of patients after resection, which is associated with a worse tumor stage and grade [9]. To further exacerbate the situation, at least some malignancies of the urinary tract are age-related, therefore, it is very plausible Glo1 activity can be regulated through several mechanisms including gene expression regulation [21,26,35,36] and post-translational modifications such as phosphorylation, NO-mediated modification and glutathionylation [21,[38][39][40][41]. Glo2 expression can be upregulated by the transcription factors p63 and p73 [42], steroid hormones [35], androgen receptor [37] and PTEN/PI3K/AKT/mTOR signalings [36].…”

“…To further exacerbate the situation, at least some malignancies of the urinary tract are age-related, therefore, it is very plausible Glo1 activity can be regulated through several mechanisms including gene expression regulation [21,26,35,36] and post-translational modifications such as phosphorylation, NO-mediated modification and glutathionylation [21,[38][39][40][41]. Glo2 expression can be upregulated by the transcription factors p63 and p73 [42], steroid hormones [35], androgen receptor [37] and PTEN/PI3K/AKT/mTOR signalings [36]. Extensive information about physical and chemical properties of glyoxalases has been largely described in excellent previous reviews [43][44][45][46][47][48].…”