TRPM channels in human cancers: regulatory mechanism and therapeutic prospects

Abstract

The transient receptor potential melastatin (TRPM) channel family has been previously implicated in various diseases, including those related to temperature sensing, cardiovascular health, and neurodegeneration. Nowadays, increasing evidence indicates that TRPM family members also play significant roles in various types of cancers, exhibiting both pro- and anti-tumorigenic functions. They are involved in tumor cell proliferation, survival, invasion, and metastasis, serving as potential diagnostic and prognostic biomarkers for cancer. This paper begins by describing the structure and physiological functions of the TRPM family members. It then outlines their roles in several common malignancies, including pancreatic, prostate, colorectal, breast, brain cancer, and melanoma. Subsequently, we focused on investigating the specific mechanisms by which TRPM family members are involved in tumorigenesis and development from both the tumor microenvironment (TME) and intracellular signaling. TRPM channels not only transmit signals from the TME to regulate tumor cell functions, but also mediate extracellular matrix remodeling, which is conducive to the malignant transformation of tumor cells. Importantly, TRPM channels depend on the regulation of the inflow of various ions in cells, and participate in key signaling pathways involved in tumor progression, such as Wnt/β-catenin, MAPK, PI3K/AKT, p53, and autophagy. Finally, we summarize the current strategies and challenges of targeting TRPM channels in tumor treatment, and discuss the feasibility of combining targeted TRPM channel drugs with cancer immunotherapy.

Keywords: Autophagy; Cancer progression; Signaling pathway; TRPM channels; Targeted tumor therapy; Tumor microenvironment.

Fig. 1

The structure of TRPM channels. The N-terminal region consists of four structural domains called the melastatin homology region (MHR). These domains form pockets that participate in channel formation and the perception of external stimuli [15]. The transmembrane domain (TMD) contains six transmembrane helices (S1-S6). The S4 helix functions as a voltage sensing domain associated with channel activation, while the P-loop between S5 and S6 acts as the ion conduction pore [16]. The C-terminal region comprises a highly conserved TRP helical domain and a coiled-coil domain implicated in the formation of polymer complexes [17]

Fig. 2

The effect of TRPM channels on tumor microenvironment. TRPM channels in tumor cells can integrate signals from TME and regulate interaction between tumor cells and TME. 1) TRPM2. a TRPM2 channels induce Ca²⁺ inward flow to initiate the apoptotic cascade in tumor cells in response to ROS signaling in TME. b TRPM2 is activated by H₂O₂ secreted by neutrophils within the TME, enabling neutrophils to approach and kill tumor cells by promoting the expression of the chemokine CXCL2. c TRPM2 is activated by the oxidizing agent Chl-T and relies on Ca²⁺ influx to stimulate the potassium channels BK and KCa3.1, all of which are jointly involved in melanoma progression. 2) TRPM5. TRPM5 mediates the expression of MMP-9 induced by extracellular acidic PH, facilitating lung metastasis of melanoma. 3) TRPM7. a TRPM7 depends on Mg²⁺ inward flow and promotes ECM degradation through the Hsp90α/uPA/MMP2 axis, encouraging cancer cell invasion and metastasis. b TGFβ can stimulate the expression of TRPM7 and boost the EMT process of cancer cells through TRPM7-mediated Mg²⁺ influx. c TRPM7 inhibits RACK1-mediated degradation of HIF-1α, promoting migration and invasion of cancer cells under hypoxic conditions. d TRPM7-dependent calcium signaling enhances the O-GlcNAcylation levels of c-Myc and Cav-1 in cells, preventing their degradation and supporting tumor metastasis

Fig. 3

The effect of TRPM channels on signal pathways related to tumor progression. TRPM channels are widely involved in tumor cell proliferation, invasion, and metastasis by regulating signaling pathways related to tumor cell progression. (1) Wnt/β-catenin signaling pathway. Through the Ca²⁺/calmodulin-EGFR signaling axis, TRPM4 controls the activities of AKT1 and GSK-3β, facilitating β-catenin entry into the nucleus. (2) MAPK signaling pathway. a TRPM2 activates the MEK pathway by initiating PKC and inhibits JNK activation by reducing ROS and RNS levels in cells. b TRPM7 relies on calcium signaling to hinder the ERK1/2 pathway. c TRPM8 inhibits JNK and p38 MAPK pathways. 3) PI3k/AKT signaling pathway. a TRPM1-dependent calcium signaling activates AKT by rousing CaMKIIδ. b TRPM2 inhibits the activity of PTEN, a negative regulator of PI3k/AKT signaling pathway, by mediating calcium influx in cells. c TRPM4 upregulates intracellular Ca²⁺ levels to induce calpain-mediated focal adhesion kinase (FAK) hydrolysis, obstructing the PI3K/AKT/mTOR signaling cascade. d TRPM7 activates the PI3K/AKT signaling pathway through magnesium and calcium signaling. 4) HIF-1α signaling pathway. In addition to preventing RACK1-mediated HIF-1 degradation, TRPM7 can also slow down HIF-1 degradation by impeding AMPK activity. 5) Calcineurin/NFAT signaling pathway. Both TRPM7 and TRPM8 activate the calcium-regulated phosphatase/NFAT signaling pathway to dephosphorylate NFAT and facilitate its movement into the nucleus. 6) p53 signaling pathway. TRPM7 promotes MDM2-mediated p53 degradation by influencing Mg²⁺ influx, or promotes MDMX-mediated inhibition of p53 transcriptional activity by affecting Zn²⁺ influx

Fig. 4

The effect of TRPM channels on autophagy in tumor cells. The effect of TRPM channels on the autophagy process in tumor cells varies by cell type and status. 1) TRPM2. a Under oxidative stress, TRPM2 activates CAMK2 by Ca²⁺ influx, inhibiting VPS34 complex binding by phosphorylating Beclin1, which hinders autophagy (marked by blue arrows). b TRPM2 enhances the expression of BNIP3 and ATGs in a JNK-dependent manner, promoting autophagy. 2) TRPM3. TRPM3 activates CaMKK2 to promote AMPK activation in a Ca²⁺-dependent manner, supporting autophagy. 3) TRPM7. a Similar to TRPM3, TRPM7 boosts autophagy by activating CAMKK2. b TRPM7 inhibits the fusion of autophagosomes and lysosomes by releasing Zn²⁺ in vesicles. 4) TRPM8. TRPM8 contributes to autophagy by activating AMPK