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    • Hypoxia has been shown to affect miR

    2022-03-18

    Hypoxia has been shown to affect miR-155 expression that can induce autophagy in nasopharyngeal and cervical carcinoma cells [334]. Suppression of miR-155 inhibited hypoxia-induced autophagy. miR-155 targeted mRNAs involved in the PI3K/PTEN/Akt/mTORC1 pathway including: Ras homolog enriched in Folinic acid (RHEB), rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR),and ribosomal protein S6 kinase beta-2 (RPS6KB2). miR-155 had effects on cell proliferation [334]. In some cell types, miR-155 and miR-31 may inhibit PP2A activity which results in decreased GSK-3beta activity which has effects on autophagy. This also alters the Wnt signaling pathway [335]. A diagram of the effects of miRs on autophagy and Wnt signaling is presented in Fig. 12.
    Abnormal activation of PI3K/PTEN/Akt/mTORC1 and Ras/Raf/MEK/ERK pathways can result in deregulated GSK-3 activity and drug resistance These pathways are two of the most frequently activated signaling pathways due to mutations/amplification of upstream growth factor receptors in numerous cancers (Fig. 13). For example, components of the EGFR pathway are mutated/amplified in many different cancers [38], [151]. Other growth factors and receptors also cause activation of these singling pathways [38], [151]. In addition, other key signaling pathways are activated by these mutations and gene deregulations such as the Jak/STAT pathway [336]. Dysregulation of these pathways will alter GSK-3 activity by various kinases and phosphatases as well as miRs [3], [4], [5], [6], [337]. A diagram of how these mutations can alter gene expression is presented in Fig. 13. The PIK3CA gene is one of the most frequently mutated genes in breast cancer [338]. Mutations at PIK3CA often serve to stimulate its activity [3], [4], [5], [6], [338]. Various effective small molecule inhibitors are being developed to suppress the activity of this pathway, as it is a key therapeutic target [338], [339], [340], [341], [342], [343], [344], [345]. The PTEN phosphatase is also mutated frequently in human cancer [346], [347]. PTEN is a tumor suppressor gene and is often silenced by mutations or epigenetic mechanisms in cancer. PTEN inhibitors are also being developed [348], [349]. In particular, pharmacological inhibition of PTEN with the water-soluble vanadium-based complex (VO-OHpic), a potential antidiabetic drug [350], has recently been discovered to trigger induction of senescence in PTEN+/− prostate tumor cells, with no deleterious effect on PTEN WT cells [351]. This senescence response, referred to as PTEN-induced cellular senescence (PICS), was observed only in cells with partial PTEN activity (heterozygous). VO-OHpic treatment also induced cellular senescence in HCC cells with low endogenous PTEN levels [352]. Furthermore in HCC cells, treatment with VO-OHpic induced cell cycle arrest and expression of senescence-associated secretory phenotype (SASP) pro-inflammatory cytokine and protease mRNAs, IL-8 and MMP9 respectively. These findings indicated that VO-OHpic could be developed as a potential “pro-senescence” anti-cancer drug for the treatment of cancers with reduced PTEN expression. VO-OHpic has been also used in combination with 3-deazaneplanocin A (DZNep), a potent enhancer of zeste homolog 2 (EZH2) that is a histone-lysine N-methyltransferase enzyme inhibitor, to demonstrate the role of PTEN in polycomb repressive complex-2 (PRC2)-mediated apoptosis of colon cancer stem cells [353]. PTEN inhibition by VO-OHpic has a cardioprotective effect, in that VO-OHpic protects cardiomyocytes against cell death induced by ischemia and reperfusion [354]. In addition, it has been reported that myocardial infarct size was significantly reduced in VO-OHpic-pretreated mice [355]. Phospholipases, phosphatases and lipid kinases also play key roles in the regulatory circuits [356], [357], [358], [359], [360], [361] and inhibitors to these enzymes are being developed. Mutations at KRAS are detected in many different cancers. KRAS mutations are frequently observed in pancreatic cancer [115], [116]. In addition, RAS-related genes are also important in human cancer and other disease [362], [363]. One consequence of KRAS mutations is the activation of the Raf/MEK/ERK cascade which in turn can activate the transcription factor ETS which can induce GSK-3 transcription. GSK-3 can then induce the inhibitor kappa kinase (IKK) that results in phosphorylation of inhibitor kappa-B (I-kappaB) and activation of nuclear factor kappa B (NF-kappaB) that induces the transcription of many genes implicated in inflammation and cancer metastasis [364], [365], [366], [367], [368], [369].