Organelles Ca2+ redistribution contributes to cadmium-induced EMT of renal cancer cells through p-cPLA2-mediated arachidonic acid release

Abstract

Cadmium ion (Cd²⁺) is a non-essential metal that can increase cancer risk, including potentially renal cell carcinoma (RCC), though this link is not definitive. Cd²⁺ exposure impairs fatty acid metabolism in the kidneys, particularly affecting arachidonic acid (AA) levels, which are crucial for health. Previous studies have suggested that Cd²⁺-altered the AA metabolism associates with renal dysfunction. However, the role and mechanism of Cd²⁺-regulated AA source in promoting RCC progression are still unclear. This study aims to investigate how Cd²⁺ exposure affects AA levels in renal cancer cells and its role in promoting cell migration. Cd²⁺ exposure increases AA levels through cPLA₂-mediated release. It also induces calcium ion (Ca²⁺) redistribution from the endoplasmic reticulum (ER) to mitochondria, activating the p38 MAPK/cPLA₂ signaling pathway, and epithelial-mesenchymal transition (EMT) of Caki-1 cells. Cd²⁺-induced ER Ca²⁺ release, p38 MAPK/cPLA₂ signaling activation, AA levels, and EMT of Caki-1 cells were effectively reversed by siRNA knockdown of IP3R. Both exogenous AA treatments and Cd²⁺-induced AA metabolite PGD2 promoted EMT and cell migration of Caki-1 cells. This study highlights Cd^2+’s impact on fatty acid metabolism and organelle function in renal cancer cells, identifying potential therapeutic targets for RCC.