Abstract
Transient Receptor Potential (TRP) cations channels, as key regulators of intracellular calcium homeostasis, play a central role in the essential hallmarks of cancer. Among the multiple pathways in which TRPs may be involved, here we focus our attention on the ones involving small guanosine triphosphatases (GTPases), summarizing the main processes associated with the metastatic cascade, such as migration, invasion and tumor vascularization. In the last decade, several studies have highlighted a bidirectional interplay between TRPs and small GTPases in cancer progression: TRP channels may affect small GTPases activity via both Ca2+-dependent or Ca2+-independent pathways, and, conversely, some small GTPases may affect TRP channels activity through the regulation of their intracellular trafficking to the plasma membrane or acting directly on channel gating. In particular, we will describe the interplay between TRPC1, TRPC5, TRPC6, TRPM4, TRPM7 or TRPV4, and Rho-like GTPases in regulating cell migration, the cooperation of TRPM2 and TRPV2 with Rho GTPases in increasing cell invasiveness and finally, the crosstalk between TRPC1, TRPC6, TRPM8, TRPV4 and both Rho- and Ras-like GTPases in inducing aberrant tumor vascularization.
Highlights
Ca2+ signaling plays a central role in the regulation of many important cellular functions and not surprisingly, a dysregulation of Ca2+ homeostasis has been observed in various pathological conditions, including tumorigenesis (Monteith et al, 2017)
All the steps involved in metastatic cascade (EMT, cell migration, invasion and tumor vascularization) are regulated by the intracellular Ca2+ concentration (Berridge et al, 2003) and by the Transient Receptor Potential (TRP)-mediated calcium influx (Fels et al, 2018), as well as by the most important small guanosine triphosphatases (GTPase) (Rho-like and Ras-like) involved in cytoskeletal dynamics and cell polarity (Ungefroren et al, 2018)
There are not robust data on GTPases-mediated TRPC6 functions in angiogenesis, recently Zahra and coworkers defined an important role of RhoA in endothelial cell (EC) proliferation, migration, invasion and sprouting triggered by important angiogenesis inducers, including vascular endothelial growth factor (VEGF) (Zahra et al, 2019), suggesting a possible interplay between TRPC6 and RhoA in VEGF-induced angiogenesis
Summary
Ca2+ signaling plays a central role in the regulation of many important cellular functions and not surprisingly, a dysregulation of Ca2+ homeostasis has been observed in various pathological conditions, including tumorigenesis (Monteith et al, 2017). All the steps involved in metastatic cascade (EMT, cell migration, invasion and tumor vascularization) are regulated by the intracellular Ca2+ concentration (Berridge et al, 2003) and by the TRP-mediated calcium influx (Fels et al, 2018), as well as by the most important small GTPases (Rho-like and Ras-like) involved in cytoskeletal dynamics and cell polarity (Ungefroren et al, 2018).
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