TRP Channels in Cancer: Signaling Mechanisms and Translational Approaches

Abstract

Ion channels play a crucial role in a wide range of biological processes, including cell cycle regulation and cancer progression. In particular, the transient receptor potential (TRP) family of channels has emerged as a promising therapeutic target due to its involvement in several stages of cancer development and dissemination. TRP channels are expressed in a large variety of cells and tissues, and by increasing cation intracellular concentration, they monitor mechanical, thermal, and chemical stimuli under physiological and pathological conditions. Some members of the TRP superfamily, namely vanilloid (TRPV), canonical (TRPC), melastatin (TRPM), and ankyrin (TRPA), have been investigated in different types of cancer, including breast, prostate, lung, and colorectal cancer. TRP channels are involved in processes such as cell proliferation, migration, invasion, angiogenesis, and drug resistance, all related to cancer progression. Some TRP channels have been mechanistically associated with the signaling of cancer pain. Understanding the cellular and molecular mechanisms by which TRP channels influence cancer provides new opportunities for the development of targeted therapeutic strategies. Selective inhibitors of TRP channels are under initial scrutiny in experimental animals as potential anti-cancer agents. In-depth knowledge of these channels and their regulatory mechanisms may lead to new therapeutic strategies for cancer treatment, providing new perspectives for the development of effective targeted therapies.

Targeting TRPV4 Channels for Cancer Pain Relief

“…Similarly, different TRPV isoforms have been involved in the development and progression of several types of cancers, including oral, bone, colon, prostate, pancreatic, and skin. Altogether, the de-regulated expression of these channels has emerged as a crucial factor that influences multiple hallmarks of cancer biology, covering critical processes such as tumor cell proliferation, migration, invasion, angiogenesis, and resistance to therapeutic measures [62,66]. Recent reports have proposed the existence of an intricate connection between TRPV4 activation and the tumor dynamic microenvironment, suggesting that during this complex process, TRPV4 channels sensitized by different stimuli, including matrix stiffness, are rapidly activated and became critical for the arrangement of the metastatic cascade in a plethora of tumors, such as breast, endometrial, gastric, and colon cancer, as well as in the induction of the migratory phenotype in melanoma cells [67,68].…”

“…Regarding this, TRPV4 has been increasingly recognized, especially its possible role in suppressing cancer cell metastasis. Modulating the activity of these channels could lead not only to the inhibition of tumor cells' growth but also to the increased efficacy of existing therapies on TRPV4-overexpressing cells [19,61,66,67].…”

“…As evidenced by several recent reviews, these modulators have shown promising characteristics to manage a variety of pain types, including inflammatory, neuropathic, and visceral pain. Regardless of the clinical relevance, however, the precise mechanism of action leading to CIPN symptom amelioration remains uncertain [66,117]. Therefore, research in this field continues to unfold, and further elucidation of TRP channels' molecular function and their contribution to CIPN pathophysiology is warranted.…”

“…Moreover, TRPV4 activation in dural afferents leads to hind paw and facial allodynia in mice, while mechanical hyperalgesia is triggered by PAR-2 activation in primary afferent neurons expressing TRPV4. These ion channels are also expressed in immune cells, where their activation results in Ca 2+ influx [66,82,122]. Considering this, it is pertinent to investigate the processes through which TRPV4 is involved in cancer pain.…”

Transient Receptor Potential Ankyrin 1 (TRPA1) Modulation by 4-Hydroxynonenal (4-HNE) in Pancreatic Adenocarcinoma Cell Lines: Putative Roles for Therapies

“…In the last decade, many groups have probed several genes or proteins to salvage the therapeutic limitations induced by the late detection of PDAC, when most patients are diagnosed with metastases. Among them are members of the superfamily of transient receptor potential channels (TRP), indicated as putative targets in those cases where overexpression is measurable [ 3 ]. Lately, new perspectives arose when some members of the TRP family were discovered to be reactive oxygen species (ROS) sensors.…”