Calcium sensing receptor suppresses human pancreatic tumorigenesis through a novel NCX1/Ca(2+)/β-catenin signaling pathway.
The calcium sensing receptor (CaSR) is functionally expressed in normal human pancreases, but its pathological role in pancreatic tumorigenesis is currently unknown. We sought to investigate the role of CaSR in pancreatic cancer (PC) and the underlying molecular mechanisms. We revealed that the expression of CaSR was consistently downregulated in the primary cancer tissues from PC patients, which was correlated with tumor size, differentiation and poor survival of the patients. CaSR activation markedly suppressed pancreatic tumorigenesis in vitro and in vivo likely through the Ca(2+) entry mode of Na(+)/Ca(2+) exchanger 1 (NCX1) to induce Ca(2+) entry into PC cells. Moreover, NCX1-mediated Ca(2+) entry resulted in Ca(2+)-dependent inhibition of β-catenin signaling in PC cells, eventually leading to the inhibition of pancreatic tumorigenesis. Collectively, we demonstrate for the first time that CaSR exerts a suppressive function in pancreatic tumorigenesis through a novel NCX1/Ca(2+)/β-catenin signaling pathway. Targeting this specific signaling pathway could be a potential therapeutic strategy for PC.
Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
Bo
B
Tang
Department of Medicine, University of California, San Diego, CA, USA.
Jimmy Y C
JY
Chow
Department of Medicine, University of California, San Diego, CA, USA.
Tobias Xiao
TX
Dong
Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
Shi-Ming
SM
Yang
Cancer Research Center, Shenzhen University, Shenzhen, China.
De-Sheng
DS
Lu
Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. Electronic address: jcarethe@med.umich.edu.
John M
JM
Carethers
Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Department of Medicine, University of California, San Diego, CA, USA. Electronic address: h2dong@ucsd.edu.
Hui
H
Dong
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D044169:Receptors, Calcium-Sensing / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism*; D013096:Spermine / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D060449:Wnt Signaling Pathway / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; C095550:CASR protein, human; C495270:CTNNB1 protein, human; D044169:Receptors, Calcium-Sensing; D019831:Sodium-Calcium Exchanger; D051176:beta Catenin; C110374:sodium-calcium exchanger 1; D013096:Spermine
Ca(2+) signaling; CaSR; NCX1; Pancreatic cancer; β-catenin