Mechanically activated ion channel Piezo1 contributes to melanoma malignant progression through AKT/mTOR signaling

Abstract

Melanoma is a highly aggressive cancer that can metastasize at early stage. The aim of this study is to clarify the role of Piezo1 and its potential mechanism in regulating the malignant phenotypes of melanoma. In the present study, we first showed that Piezo1 was abnormally expressed in melanoma, which accelerated the malignant progression by activating AKT/mTOR signaling. Firstly, we found that Piezo1 was upregulated in melanoma and associated with poor survival. Additionally, Piezo1 knockdown significantly weakened intracellular calcium signal and viability of melanoma cells. Furthermore, Piezo1 knockdown inhibited the transendothelial migration and invasion in vitro, as well as metastasis in vivo. Mechanistically, we found that Piezo1 activated AKT/mTOR signaling to maintain malignant phenotypes of melanoma. Therefore, Piezo1 acts as an oncogene in melanoma cells and provides a novel candidate for melanoma diagnosis and treatment.

Promotion of Melanoma Cell Proliferation by Cyclic Straining through Regulatory Morphogenesis

“…It was interesting that with the treatment of cyclic straining, the positive effect on A375 cells was greater than on B16 cells. In a previous report, after the interference of mechanosensing ion channel Piezo 1, the proliferation ability of melanoma cells was inhibited [ 35 ]. Specifically, the decreased positive ratio of Ki67 in A375 cells was greater than the decreased value in B16 cells.…”

The mechanosensitive TRPV2 calcium channel promotes human melanoma invasiveness and metastatic potential

“…We, however, know that the dynamic endosomal‐PM translocation of TRPV2, regulating its activity (Kojima & Nagasawa, 2014 ), can be induced by mechanical cues (Karki & Tojkander, 2021 ). The cAMP‐dependent protein kinase A (PKA) and the PI3K/AKT pathways have been shown to regulate TRPV2 trafficking to the PM (Stokes et al , 2004 ; Nagasawa & Kojima, 2015 ), and intriguingly both pathways are, respectively, negatively or positively regulated by PIEZO1 (Hung et al , 2016 ; Zhang et al , 2022 ), a stretch‐activated channel involved in adhesion maturation and confinement‐induced migration (Canales Coutino & Mayor, 2021 ; Yao et al , 2022 ; Zhang et al , 2022 ).…”

Pleiotropic physiological functions of Piezo1 in human body and its effect on malignant behavior of tumors

“…Similarly, in the case of melanoma, Piezo1 promotes the malignant progression of the disease through Akt/mTOR signaling. Piezo1 ion channel protein can regulate calcium concentration in melanoma cells, further increasing the activation level of the PI3K/Akt/mTOR pathway, thereby regulating the malignant progression of melanoma ( Zhang S. et al, 2022 ).…”

“…Alterations in Piezo1 expression have been observed in several tumors by regulating key cell cycle regulators and thus affecting tumor cell proliferation. In melanoma cells, knockdown of Piezo1 resulted in alterations in cell cycle-related genes, with a significant decrease in the expression of key effectors CDK2 and CyclinD1 genes and an increase in the expression of classical tumor suppressors P21 and PTEN ( Zhang S. et al, 2022 ). In addition, Piezo1 knockdown induced G1 phase block in gastric cancer cells and downregulated phosphorylated Rb, Cyclin D1, CDK4, and CDK6 ( Zhang et al, 2018 ), suggesting that Piezo1 is required for gastric cancer cell proliferation.…”

“…Tumor metastasis is a multi-step cascade process, which can be roughly divided into local invasion of tumors, internal infiltration into the peripheral vasculature and lymphatics, survival in the circulatory system and metastasis, extravasation from the vascular lumen into the parenchymal tissues, and finally adaptation to the microenvironment of the metastasis to complete colonization ( Talmadge and Fidler, 2010 ). A large body of literature shows that Piezo1 plays an important role in tumor migration ( Li et al, 2015 ), extravasation ( Zhang S. et al, 2022 ), and distant metastasis ( Lin CY. et al, 2022 ), and promotes local invasion and distant metastasis of tumors ( Figure 4 ).…”