Transient receptor potential vanilloid 1 promotes EGFR ubiquitination and modulates EGFR/MAPK signalling in pancreatic cancer cells

Abstract

Transient receptor potential vanilloid-1 (TRPV1) was first identified in sensory neurons, where it was suggested as a therapeutic target for pain relief. Here, we show that TRPV1 is expressed in the pancreatic cancer cell line, PANC-1; that epidermal growth factor receptor (EGFR) expression is downregulated by overexpression or agonist-induced activation of TRPV1; and conversely, that EGFR expression is increased after silencing TRPV1. Furthermore, TRPV1 overexpression inhibits cell proliferation and significantly reduces the mRNA levels of two oncogenes, KRAS and AKT2. More importantly, TRPV1 downregulates EGFR levels by inducing EGFR ubiquitination and degradation, which modulate EGFR/MAPK signalling in pancreatic cancer cells. These results illustrate the regulation and mechanism of TRPV1 on EGFR in pancreatic cancer cells and may provide new ideas for the design of novel antitumor drugs targeting EGFR.Significance of the study: We investigated the effect and mechanism of TRPV1 on EGFR-mediated proliferation and transformation of pancreatic cancer cells, with the aim of providing new ideas and experimental evidence for the application of strategies that promote EGFR degradation to treat pancreatic cancer. K E Y W O R D SEGFR/MAPK signalling, epidermal growth factor receptor (EGFR), pancreatic cancer, transient receptor potential vanilloid 1 (TRPV1), ubiquitination

Ion Channel Signature in Healthy Pancreas and Pancreatic Ductal Adenocarcinoma

“…Recently, it has been shown that TRPV1 regulates the Epidermal Growth Factor Receptor (EGFR) in PANC-1 cell line (Huang et al, 2020). In this study, an overexpression of TRPV1 has been associated with a decrease in protein expression of EGFR in PANC-1.…”

“…The membranous fractions of EGFR were reduced, while the cytoplasmic were increased compared to the control (Huang et al, 2020). This indicates that TRPV1 promotes EGFR ubiquitination and thereby a downregulation of EGFR activity, resulting in EGFR cytoplasmic translocation and degradation, which was found to be mainly through the lysosomal pathway (Huang et al, 2020). Furthermore, it was shown that TRPV1 overexpression inhibited proliferation, probably through the MAPK signaling pathway.…”

“…TRPV1 has shown to be related to oncogenesis and is expressed in different types of cancer (Domotor et al, 2005;Lazzeri et al, 2005;Sanchez et al, 2005;Miao et al, 2008;Morelli et al, 2014;Vercelli et al, 2014). TRPV1 can be activated by multiple pathways, which can promote pancreatic inflammation and pain, but also pancreatic cancer (Hartel et al, 2006;Huang et al, 2020). TRPV1 was shown to be upregulated at the mRNA and protein level in PDAC tissue compared to normal pancreatic tissue (Hartel et al, 2006).…”

“…Furthermore, it was shown that TRPV1 overexpression inhibited proliferation, probably through the MAPK signaling pathway. Overexpression of TRPV1 resulted in decreased mRNA levels of KRAS and AKT2 and a treatment with EGF reduced the protein expression of ERK, JNK, and CREB, suggesting that a TRPV1 overexpression decreases EGFR/MAPK dependent proliferation in PANC-1 cells (Huang et al, 2020). The two above mentioned studies show contrary results in form of how the expression of TRPV1 is related to proliferation.…”

TRP Channels in Digestive Tract Cancers

“…Either the overexpression or agonist-induced activation of TRPV1 reduced the expression of epidermal growth factor receptor (EGFR), due to its ubiquitination. Additionally, TRPV1 reduced mRNA expression of two oncogenes, KRAS and AKT2 [107]. Another member of the TRPV subfamily, TRPV6, is expressed in BON-1 cell line on mRNA and protein level, and it regulates Ca 2+ levels.…”