Nociceptive transient receptor potential canonical 7 (TRPC7) mediates aging‐associated tumorigenesis induced by ultraviolet B

Abstract

Aging, cancer, and longevity have been linked to intracellular Ca2+ signaling and nociceptive transient receptor potential (TRP) channels. We found that TRP canonical 7 (TRPC7) is a nociceptive mechanoreceptor and that TRPC7 channels specifically mediate the initiation of ultraviolet B (UVB)‐induced skin aging and tumor development due to p53 gene family mutations. Within 30 min after UVB irradiation, TRPC7 mediated UVB‐induced Ca2+ influx and the subsequent production of reactive oxygen species in skin cells. Notably, this function was unique to TRPC7 and was not observed for other TRP channels. In TRPC7 knockout mice, we did not observe the significant UVB‐associated pathology seen in wild‐type mice, including epidermal thickening, abnormal keratinocyte differentiation, and DNA damage response activation. TRPC7 knockout mice also had significantly fewer UVB‐induced cancerous tumors than did wild‐type mice, and UVB‐induced p53 gene family mutations were prevented in TRPC7 knockout mice. These results indicate that TRPC7 activity is pivotal in the initiation of UVB‐induced skin aging and tumorigenesis and that the reduction in TRPC7 activity suppresses the UVB‐induced aging process and tumor development. Our findings support that TRPC7 is a potential tumor initiator gene and that it causes cell aging and genomic instability, followed by a change in the activity of proto‐oncogenes and tumor suppressor genes to promote tumorigenesis.

Redox and mTOR-dependent regulation of plasma lamellar calcium influx controls the senescence-associated secretory phenotype

“…53 TRPC7 is showed to involved in initiation of UVB-induced aging and TRPC7 knocked down can suppress the UVB-induced aging processes. 54 Mouse vascular endothelial cells lacking TRPC5 display reduced β-galactosidase staining, implicating in the involvement of TRPC5 in development of senescence. 55…”

Calcium Channels: Noteworthy Regulators and Therapeutic Targets in Dermatological Diseases

“…Moreover, a novel TRPV1-inhibiting peptide was demonstrated to attenuate UV-induced erythema and the expression of MMP-1, MMP-2, IL-6, and IL-8 in human skin in vivo ( Kang et al, 2017 ). Recently, a study found TRPC7 mediated UVB-induced Ca 2+ influx, UVB-induced ROS production, and UVB-induced epidermal aging in mice ( Hsu et al, 2020 ). These findings suggest that inhibition of specific TRP channels may delay skin aging.…”

A novel strategy for treating cancer: understanding the role of Ca2+ signaling from nociceptive TRP channels in regulating cancer progression

“…Although numbers of TRP channels are identified by their characteristics and functions, several TRP channels are characterized by nociceptive TRP channels, including TRPA1, TRPC1/C3/C5/C6/C7, TRPM2/M3/M8 and TRPV1/V2/V3/V4, which are involved in the nociceptive pathway [19]. Interestingly, these nociceptive TRP channels in non-excitable or excitable cells potentially initiate the aging process due to excess Ca 2+ signaling from active nociceptive TRP channels upon continual environmental stimuli [11][12][13][14][15]. Environmental stimuli, such as bacterial endotoxins, oncovirus, di-(2-ethylhexyl)-phthalate (DEHP), particulate matters (PMs) or ultraviolet radiation have responding nociceptive TRP channels.…”

“…The therapeutic targeting of Ca 2+ signaling provides a novel approach for treating cancer. Recently, nociceptive transient receptor potential (TRP) channels, which belong to a special group of TRP channels, have been involved in the nociceptive pathway and include members of the TRP ankyrin (TRPA), and TRP canonical (TRPC), TRP mucolipin (TRPM) and TRP vanilloid (TRPV) subfamilies that potentiate regulation of the aging process and tumorigenesis by Ca 2+ signaling [11][12][13][14][15]. This is different from the classical function of nociceptive TRP channels in excitable cells (neurons, muscle cells and some endocrine cells) that causes an influx of ions through the cell membrane to induce a depolarization of the cell which in turn triggers action potentials [16].…”