Over the last few years experimental evidence for the

Over the last few years, experimental evidence for the involvement of Epac1 in cancer progression is beginning to emerge (Almahariq et al., 2015, Banerjee and Cheng, 2015, Parnell et al., 2015, Parnell et al., 2015, Schmidt et al., 2013). For example in melanoma cells, silencing of Epac1 attenuates migration in vitro and metastasis in vivo (Baljinnyam et al., 2009, Baljinnyam et al., 2010, Baljinnyam et al., 2011, Baljinnyam et al., 2014, Gao et al., 2006). Similarly, in pancreatic adenocarcinoma, activation of Epac1 enhances migration while inhibition or silencing of Epac1 attenuates migration (Almahariq et al., 2013, Burdyga et al., 2013). Indeed, mice deficient for Epac1 exhibit a lower level of metastasis as shown by in vivo imaging of xenografts (Almahariq et al., 2015, Almahariq et al., 2015). Seemingly on the contrary, pharmacological activation of Epac1 decreases cell migration in prostate cancer 4SC-202 (Grandoch et al., 2009). However, later studies suggested that inhibition of migration was the result of nonspecific PKA activation rather than Epac activation as silencing of Epac had no effect on the Epac agonist-induced decrease in cell migration, while simultaneous application of the Epac agonist with a PKA inhibitor reversed the effect (Menon et al., 2012). In line with these findings, several studies in multiple different cancer cell lines have shown that PKA and Epac exert opposite effects on cell migration (Burdyga et al., 2013, Lee et al., 2014). Crosstalk between Epac1 and Rac1 in cancer cells has been described in cervical carcinoma and fibrosarcoma in which Epac1 activation results in enhanced migration in a Rac1-dependent manner (Harper et al., 2010, Lee et al., 2014). The Rac effector PAK1 has been shown in ecent studies to induce β-catenin phosphorylation on serine 675, a residue that is once phosphorylated, stabilizes β-catenin and enhances nuclear β-catenin accumulation (Fig. 2) (Arias-Romero et al., 2013, Zhu et al., 2012). Thus, crosstalk between Epac1 and Rac1 could result in increased stability of free cytosolic β-catenin and nuclear accumulation.
Hypoxia-driven metastasis Inside a tumor, carcinoma cells also undergo EMT, however in contrast to cells that are more in the periphery of the tumor, the transition from an epithelial-like to a mesenchymal-like cell depends on different cues. For example, inside the tumor, hypoxia drives EMT through regulation of the EMT transcriptional regulator Twist (Peinado and Cano, 2008, Yang et al., 2008). Therefore, the occurrence of hypoxia is linked to increased metastatic potential (Gilkes et al., 2014, Gilkes et al., 2014). Generally, hypoxia leads to the induction of the α subunit of the heterodimeric transcription factor Hif-1 (Brown & Wilson, 2004). Under conditions of abundant oxygen availiability, cytosolic Hif1α levels are under control by the sequential action of prolyl hydroxylases, which hydroxylate Hif1α, and Von Hippel-Lindau protein (pVHL), an ubiquitin ligase that targets Hif1α for proteasomal degradation. However, under hypoxic conditions, prolyl hydroxylases become inactive and Hif1α can accumulate within the cytosol and translocate to the nucleus, where it forms a heterodimer with the β subunit and regulates transcriptional adaptations to the hypoxic environment. When hepatocellular carcinoma cells are exposed to hypoxic conditions, Rac1 and Cdc42 are activated (Hirota & Semenza, 2001). Interestingly, expression of dominant negative Rac1 or Cdc42 prevents Hif1α transcriptional activity, while expression of constitutively active Rac1 enhances Hif1α transcriptional activity (Xue et al., 2006), while conversely, dominant negative Rac1 and Cdc42 increase the expression of pVHL and thereby decrease Hif1a under hypoxia (Xue et al., 2006). In addition, studies in renal cell carcinoma have revealed that under hypoxic conditions RhoA and ROCK are also involved in the regulation of pVHL (Turcotte, Desrosiers, & Beliveau, 2004), while on the other hand, Hif1α regulates the expression and activity of RhoA and ROCK (Gilkes, Xiang, et al., 2014). Importantly, this regulation of RhoA and ROCK under hypoxia was foud to promote the formation of focal adhesions, enhance actomyosin contractility and increases overall cell motility (Gilkes, Xiang, et al., 2014). The importance of this crosstalk between RhoA/ROCK and Hif1α is nicely illustrated by a recent study showing that renal cell carcinoma cells, which are often deficient in pVHL and consequently have high levels of Hif1α, are synthetically lethal to pharmacological ROCK inhibition, a process which was dependent on upregulation of Hif1α (Thompson et al., 2017, Thompson et al., 2017). Additionally, the stabilization of Hif1α or overexpression also results in formation of invadopodia, which is accompanied by an increase in Cdc42 and β-Pix expression. When expression of β-Pix is reduced, the formation of invadopodia is decreased, suggesting the fundamental requirement for β-Pix in hypoxia-induced invadopodia formation (Md Hashim et al., 2013).