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

Abstract

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.

Identification of pharmacological inducers of a reversible hypometabolic state for whole organ preservation

“…Interestingly, our studies with cultured human cells suggest that the metabolism-suppressing effects of SNC80 were most potent in the Caco2 and Huh7 cell lines that were originally derived from more highly metabolic tumors, which is also consistent with past work suggesting that targeting of the NCX1 channel might offer a way to slow cancer growth. 42 In summary, our findings demonstrate that a small molecule drug can be used to induce a state of biostasis similar to that normally induced by cooling, and demonstrate the therapeutic potential of this type of biostasis inducer for clinical applications, such as enhanced preservation of organs. The use of a biostatic compound in combination with a self-contained transport system could potentially increase organ viability for sustained times ex vivo, thus helping to advance organ and tissue preservation for surgical transplantation.…”

“…Interestingly, our studies with cultured human cells suggest that the metabolism-suppressing effects of SNC80 were most potent in the Caco2 and Huh7 cell lines that were originally derived from more highly metabolic tumors, which is also consistent with past work suggesting that targeting of the NCX1 channel might offer a way to slow cancer growth. 42…”

NCX1/Ca2+ promotes autophagy and decreases bortezomib activity in multiple myeloma through non-canonical NFκB signaling pathway

“…Furthermore, NCX1 inhibition attenuated high Ca 2+ -induced activation of cytoprotective autophagy, thereby increasing BTZ sensitivity. To our knowledge, only a few reports have shown expression of NCX1 in several cancer cells [40][41][42]. The function of NCX1 in cancer cell development or chemosensitivity remains unknown.…”

NCX1/Ca2+ promotes autophagy and decreases bortezomib activity in multiple myeloma through non-canonical NFκB signaling pathway

“…Furthermore, NCX1 inhibition attenuated high Ca 2+ -induced activation of cytoprotective autophagy, thereby increasing BTZ sensitivity. To our knowledge, only a few reports have shown expression of NCX1 in several cancer cells [ 43 – 45 ]. The function of NCX1 in cancer cell development or chemosensitivity remains unknown.…”