NCX1 coupled with TRPC1 to promote gastric cancer via Ca²⁺/AKT/β-catenin pathway

Plasma membrane Na⁺/Ca²⁺ exchanger 1 (NCX1) is a bidirectional ion transporter to operate in Ca²⁺ entry or exit modes, and TRPC1 is Ca²⁺-permeable channel. Both NCX1 and TRPC1 play critical roles in maintaining cytosolic free Ca²⁺ ([Ca²⁺]_cyt) homeostasis in mammalian cells. Although either TRPC1 channel or Ca²⁺ entry mode of NCX1 is implicated in some tumorigenesis, it has not been explored if a coordination of NCX1 and TRPC1 involves in the pathogenesis of H. pylori-associated human gastric cancer (GC). Here we found the protein expression of NCX1 was significantly enhanced in human GC specimens, which correlated with tumor progression and poor survival in GC patients. TRPC1 and NCX1 were parallelly enhanced, co-localized and bound in human GC cells. By a functional coupling, TRPC1 drives NCX1 to the Ca²⁺ entry mode, raising [Ca²⁺]_cyt in GC cells. Moreover, CaCl₂, H. pylori and their virulence factors all enhanced expressions and activities of NCX1 and TRPC1, and evoked aberrant Ca²⁺ entry to promote proliferation, migration, and invasion of GC cells through AKT/β-catenin pathway. Tumor growth and metastasis also depended on the enhanced expression of NCX1 in subcutaneously xenografted GC mouse model. Overall, our findings indicate that TRPC1/NCX1 coupling may promote H. pylori-associated GC through the Ca²⁺/AKT/β-catenin pathway. Since the Ca²⁺ exit mode and the Ca²⁺ entry mode of NCX1 play different roles under mostly physiological and pathological conditions respectively, targeting TRPC1/NCX1 coupling could be a novel strategy for selectively blocking Ca²⁺ entry mode to potentially treat digestive cancer with less side effect.