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  • Recently it was found that hypoxia results

    2021-11-25

    Recently, it was found that hypoxia results in the phosphorylation of β-catenin at Y654 in a Src-dependent manner (Xi et al., 2013). All β-catenin phosphorylated at this residue was found complexed with Hif1α and it was demonstrated that this β-catenin phosphorylation was required for Src to promote Hif1α transcriptional activity and hypoxia-induced EMT. In mice with hypoxic pancreatic carcinoma, Hif1α and pY654-β-catenin complexes accumulate which coincided with an invasive phenotype (Xi et al., 2013). A series of recent studies on the nuclear orphan receptor Nur77, which is directly regulated by Hif1α under hypoxic conditions (Choi, Park, Kang, Liu, & Youn, 2004), have identified how Hif1α and β-catenin can enhance each other’s activity under hypoxic conditions. Hypoxia increases expression of both β-catenin and Nur77 in colorectal carcinoma cells, where expression of Nur77 correlates with invasive potential and MMP9 expression and shows an inverse correlation with E-cadherin expression (Wang et al., 2014). Interestingly, Nur77 and β-catenin confer a mutual feedback mechanism in which active β-catenin increases the expression of Nur77 through Hif1α, and hypoxia-induced Nur77 enhances β-catenin transcriptional activation. The interaction between β-catenin, Hif1α and Nur77 regulates hypoxia-induced EMT and invasive capacity of colorectal cancer 2-Deoxyadenosine 5-diphosphate receptor (To, Zeng, Zeng, & Wong, 2014). Together, these findings support the interesting interplay between hypoxia and inflammatory mediators (e.g. PGE2), that together with intracellular signaling mediators such as Rho GTPases and β-catenin, determine cellular adaptations to the hypoxic environment, including expression of angiogenic factors that stimulate the formation of new vasculature to overcome the hypoxic environment. In the context of cancer metastasis, this can become problematic, as the newly formed vasculature often displays poor maturation and is very leaky and easily accessible for disseminating cells. As the abovementioned molecular interactions under hypoxic conditions are also driving factors in EMT and the adoption of a pro-migratory, pro-invasive phenotype, these might ultimately be primary driving mechanisms of metastasis (Weis & Cheresh, 2011).
    Therapeutic perspective: targeting Rho protein networks in cancer All members of the small GTPase superfamily are generally considered to be undruggable as they lack stable cavities beside the nucleotide binding pockets. The bacterial exoenzyme C3 inhibits RhoA, RhoB and RhoC by adding an ADP-ribose moiety on asparagine residues, thereby inactivating the small GTPase (Vogelsgesang, Pautsch, & Aktories, 2007). Because of their high specificity for Rho GTPases, C3-like exoenzymes are widely used as Rho inhibitors in fundamental and preclinical studies. However, C3-like ADP-ribosyltransferases have poor cell accessibility and introduce covalent modifications, thus it is unlikely these compounds have therapeutic apllications. To elicit their effects, Rho GTPases have to be anchored to the plasma membrane by means of isoprenylation. Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the key enzyme for cholesterol biosynthesis. By inhibiting HMGCR, statins deplete the cell of the lipids required for membrane anchoring and thus induce the retention of Rho GTPases in the cytosol, thereby inhibiting their function (Gazzerro et al., 2012). Therapeutically, statins are widely used in cardiovascular disease, but statins also display promising anti-cancer capabilities by preventing tumor angiogenesis and metastasis (Demierre et al., 2005, Thurnher et al., 2012, Yeganeh et al., 2014). As different Rho GTPases are activated in response to distinct signals by specific GEFs, targeting GEFs could provide better selectivity. One example targeting a specific RhoGEF is the development of inhibitors for the RhoA GEF LARG. The compound Y16 was identified through high-throughput screening and was shown to inhibit RGS-containing RhoGEFs. In breast cancer cells, Y216 inhibits RhoA and attenuated mammary sphere formation in breast cancer cells (Evelyn et al., 2009, Shang et al., 2013). Another GEF inhibitor, Rhosin, prevents binding of RhoA to multiple RhoGEFs, including LARG, Dbl, p115RhoGEF and PDZ-RhoGEF. Recently, it was shown that Rhosin blocks chemotherapy resistance in cancer stem cells by inhibition of RhoA (Yoon et al., 2016).