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

Giorgia Chinigò^1,2, Alessandra Fiorio Pla^1,2, Dimitra Gkika^2,3,4

¹Laboratory of Cellular and Molecular Angiogenesis, Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy.

Frontiers in Pharmacology

|November 2, 2020

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.

Insights

Transient Receptor Potential (TRP) channels and small guanosine triphosphatases (GTPases) interact to drive cancer metastasis. This interplay influences cancer cell migration, invasion, and tumor vascularization.

Area of Science:

Oncology
Molecular Biology
Cell Biology

Background:

Transient Receptor Potential (TRP) cation channels regulate intracellular calcium homeostasis.
TRP channels are implicated in key cancer hallmarks.
Small guanosine triphosphatases (GTPases) are crucial for cellular processes.

Purpose of the Study:

To summarize the bidirectional interplay between TRP channels and small GTPases in cancer progression.
To focus on the role of this interaction in the metastatic cascade.
To highlight TRP-GTPase involvement in migration, invasion, and tumor vascularization.

Main Methods:

Literature review focusing on studies investigating TRP channels and small GTPases in cancer.
Analysis of Ca2+-dependent and Ca2+-independent pathways linking TRPs and GTPases.
Examination of GTPase regulation of TRP channel trafficking and gating.

Main Results:

TRP channels influence small GTPase activity via calcium-dependent and -independent mechanisms.
Small GTPases regulate TRP channel activity by controlling trafficking and gating.
Specific TRP channels (TRPC1, TRPC5, TRPC6, TRPM4, TRPM7, TRPV4, TRPM2, TRPV2, TRPM8) and GTPases (Rho-like, Ras-like) are identified in regulating migration, invasion, and vascularization.

Conclusions:

The interaction between TRP channels and small GTPases is a critical bidirectional regulator of cancer metastasis.
Targeting these pathways offers potential therapeutic strategies for inhibiting cancer progression.
Understanding this crosstalk is essential for developing novel anti-cancer treatments.

Read full analysis

Keywords:

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

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