Modulation of intracellular calcium levels by calcium lactate affects colon cancer cell motility through calcium-dependent calpain

• Published in: PloS one 2015-01, Vol.10 (1), p.e0116984-e0116984
• Main Authors: Sundaramoorthy, Pasupathi, Sim, Jae Jun, Jang, Yeong-Su, Mishra, Siddhartha Kumar, Jeong, Keun-Yeong, Mander, Poonam, Chul, Oh Byung, Shim, Won-Sik, Oh, Seung Hyun, Nam, Ky-Youb, Kim, Hwan Mook
• Format: Article
• Language: English
• Subjects: Acids; Adhesion; Calcium; Calcium (dietary); Calcium (intracellular); Calcium - metabolism; Calcium Compounds - pharmacology; Calcium influx; Calpain; Calpain - metabolism; Cancer; Cell adhesion & migration; Cell Adhesion - drug effects; Cell growth; Cell Line; Cell Movement - drug effects; Cleavage; Colon; Colon cancer; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Destabilization; Diet; Dietary supplements; Focal adhesion kinase; Focal Adhesion Protein-Tyrosine Kinases - metabolism; Homeostasis; HT29 Cells; Humans; Immunoglobulins; Intracellular; Kinases; Lactates - pharmacology; Lactic acid; MDM2 protein; Medical research; Metabolism; Metastases; Metastasis; Motility; Nuclei; Nuclei (cytology); p53 Protein; Pharmaceutical sciences; Phosphorylation; Signal Transduction - drug effects; Signaling; Tumor cell lines; Tumor proteins; Tumors; Ubiquitination; Wound Healing - drug effects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0116984

Cancer cell motility is a key phenomenon regulating invasion and metastasis. Focal adhesion kinase (FAK) plays a major role in cellular adhesion and metastasis of various cancers. The relationship between dietary supplementation of calcium and colon cancer has been extensively investigated. However, the effect of calcium (Ca2+) supplementation on calpain-FAK-motility is not clearly understood. We sought to identify the mechanism of FAK cleavage through Ca2+ bound lactate (CaLa), its downstream signaling and role in the motility of human colon cancer cells. We found that treating HCT116 and HT-29 cells with CaLa immediately increased the intracellular Ca2+ (iCa2+) levels for a prolonged period of time. Ca2+ influx induced cleavage of FAK into an N-terminal FAK (FERM domain) in a dose-dependent manner. Phosphorylated FAK (p-FAK) was also cleaved in to its p-N-terminal FAK. CaLa increased colon cancer cells motility. Calpeptin, a calpain inhibitor, reversed the effects of CaLa on FAK and pFAK cleavage in both cancer cell lines. The cleaved FAK translocates into the nucleus and modulates p53 stability through MDM2-associated ubiquitination. CaLa-induced Ca2+ influx increased the motility of colon cancer cells was mediated by calpain activity through FAK and pFAK protein destabilization. In conclusion, these results suggest that careful consideration may be given in deciding dietary Ca2+ supplementation to patient undergoing treatment for metastatic cancer.