Carbenoxolone disrupts cell migration by inhibiting the SERCA pump

Collective cell migration is a fundamental process driving tissue repair, angiogenesis, and vascular homeostasis. This coordinated movement requires both intercellular communication via gap junctions and precise intracellular Ca²⁺ signaling, largely regulated by the sarco(endo)plasmic reticulum Ca ²⁺ ATPase (SERCA) pump within the endoplasmic reticulum (ER). Historically, carbenoxolone (CBX)—a synthetic derivative of glycyrrhetinic acid—has been widely utilized as a pharmacological tool to inhibit gap junctions and dissect their role in collective cell motility. However, its molecular specificity remains highly controversial. In the present study, using different cellular models, we found that CBX drastically reduces collective cell migration by a previously undescribed function for CBX: a fast, potent, and reversible inhibition of the SERCA pump, which provokes a passive leak of the luminal ER Ca²⁺ store. Our findings suggest that the effect of CBX over many cellular responses including cell migration and communication, previously only attributed to gap junction blockade, are indeed the consequence of the disruption of intracellular Ca²⁺ homeostasis.