Abstract
Intracellular calcium (Ca2+) concentration ([Ca2+]i) is a key determinant of cell fate and is implicated in carcinogenesis. Membrane ion channels are structures through which ions enter or exit the cell, depending on the driving forces. The opening of transient receptor potential vanilloid 1 (TRPV1) ligand-gated ion channels facilitates transmembrane Ca2+ and Na+ entry, which modifies the delicate balance between apoptotic and proliferative signaling pathways. Proliferation is upregulated through two mechanisms: (1) ATP binding to the G-protein-coupled receptor P2Y2, commencing a kinase signaling cascade that activates the serine-threonine kinase Akt, and (2) the transactivation of the epidermal growth factor receptor (EGFR), leading to a series of protein signals that activate the extracellular signal-regulated kinases (ERK) 1/2. The TRPV1-apoptosis pathway involves Ca2+ influx and efflux between the cytosol, mitochondria, and endoplasmic reticulum (ER), the release of apoptosis-inducing factor (AIF) and cytochrome c from the mitochondria, caspase activation, and DNA fragmentation and condensation. While proliferative mechanisms are typically upregulated in cancerous tissues, shifting the balance to favor apoptosis could support anti-cancer therapies. TRPV1, through [Ca2+]i signaling, influences cancer cell fate; therefore, the modulation of the TRPV1-enforced proliferation–apoptosis balance is a promising avenue in developing anti-cancer therapies and overcoming cancer drug resistance. As such, this review characterizes and evaluates the role of TRPV1 in cell death and survival, in the interest of identifying mechanistic targets for drug discovery.
Highlights
Molecular mechanisms that mediate cell death and proliferation exist in balance in functional physiological systems
This review aims to characterize the molecular mechanisms through which transient receptor potential vanilloid 1 (TRPV1) exerts the mentioned effect in the interest of identifying potential targets for anti-cancer drug development
TRPV1 mRNA levels are upregulated in the U373 glioblastoma line, high-grade astrocytes, “brain tumors,” and the RT4 renal cell carcinoma line; likewise, upregulated TRPV1 protein expression is observed in the U373 and RT4 cell lines (Table 2)
Summary
TRPV1 mRNA and protein are expressed in optic, pulmonary, nervous, cardiac, skeletal, circulatory, and skin cells, as well as in numerous cancer cell lines (Table 1). TRPV1 mRNA and/or protein expression levels are downregulated in many cancerous tissues, including colorectal, nervous system, endometrial, renal and skin cancers. TRPV1 mRNA levels are upregulated in the U373 glioblastoma line, high-grade astrocytes, “brain tumors,” and the RT4 renal cell carcinoma line; likewise, upregulated TRPV1 protein expression is observed in the U373 and RT4 cell lines (Table 2). Sample NHA NHA NHA NHA Low Grade Astrocyte “Tumor Free Brain” HFF-1 HFF-1 Human Renal Sample NHUC NHUC NHUC NHUC Rat DRG NHEM NHEM NHEM NHEM NHEM NHEM NHEM NHEM NHEM NHEM Human melanocytic nevus tissues Human melanocytic nevus tissues [48]
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