TRP Channels and Small GTPases Interplay in the Main Hallmarks of Metastatic Cancer

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.

Keywords: cancer hallmarks; invasion; metastasis; migration; molecular signaling; small guanosine triphosphatases; transient receptor potential channels; tumor vascularization.

Figure 1

TRP- small GTPases signaling pathways interplay in cell migration. Cartoon depicting TRP channels signaling pathways affecting cell motility and contractility through GTPases. TRPC5, TRPM4 and TRPV4 induce the formation of protrusions and spreading via Rac1 activation in a Ca²⁺-dependent manner and at the same time Rac1 promote the translocation of TRPC5 into the plasma membrane; Rac1 and RhoA through SOCE activation induce TRPC1-mediated cell polarization for directional cell migration; TRPM7 control polarized cell movement through the regulation of Rac1 and Cdc42 in a Mg²⁺-dependent way; TRPM7, TRPV4, and TRPC6 contribute to actin dynamics and cell contractility through the Mg²⁺- or Ca²⁺-mediated activation of RhoA/ROCK pathways. FAK, focal adhesion kinase; Akt, protein-kinase B; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor; Orai1, calcium release-activated calcium channel; SK3, small conductance calcium-activated potassium channel 3; STIM, stromal interaction molecule 1; ROCK, Rho-associated protein kinase; α-SMA, alfa-smooth muscle actin; MLC, myosin light chain.

Figure 2

TRP- small GTPases signaling pathways interplay in cell invasion. Cartoon depicting TRP channels signaling pathways affecting cell invasiveness through GTPases. Rac1 promotes the translocation of TRPV2 into the plasma membrane and thus TRPV2-mediated increased in MMPs expression; TRPV2 affects also cell adhesion and invasion interfering with integrin-mediated signalling and inhibiting Rac1, RhoA, and cofilin activation by Rac1 in a Ca²⁺-dependent manner; TRPM2 and Rac1 physically interact with each other, mutually influencing their activity and lead to an increase in MMPs production; MMPs exocytosis is mediated by the Rab superfamily of small GTPases. GF, growth factor; GFR, growth factor receptor; PI3K, phosphoinositide-3 kinase; Akt, protein-kinase B; MMP, membrane-matrix metalloproteinase; ECM, extracellular matrix.

Figure 3

TRP- small GTPases signaling pathways interplay in aberrant tumor vascularization. Cartoon depicting TRP channels signaling pathways affecting tumor vascularization through GTPases. TRPV4 induces aberrant mechano-sensivity to ECM through the Ca²⁺-dependent inhibition of Rho/ROCK pathway; TRPC1 and TRPC6 enhance vessels permeability affecting cell contractility through a Ca²⁺-mediated regulation of RhoA; on the contrary, TRPM8 exerts a protective role in tumor vasculature permeability, inhibiting the store-operated RhoA activation and subsequent cell contraction; TRPM8 also inhibits ECs adhesion and migration, impairing activation of β₁-integrin through the intracellular retention of Rap1. VE-cadherin, vascular E-cadherin; FAK, focal adhesion kinase; ROCK, Rho-associated protein kinase; MLC, myosin light chain; PKCα, protein kinase C alpha; IP3R, inositol trisphosphate receptor; PAR-1, protease-activated receptor-1.