title: Modulation of intracellular calcium levels by calcium lactate affects colon cancer cell motility through calcium-dependent calpain.
abstract: 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.
authors: Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 406-840, Republic of Korea.
authors: Pasupathi
authors: P
authors: Sundaramoorthy
authors: Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 406-840, Republic of Korea.
authors: Jae Jun
authors: JJ
authors: Sim
authors: Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 406-840, Republic of Korea.
authors: Yeong-Su
authors: YS
authors: Jang
authors: Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 406-840, Republic of Korea; Department of Zoology, School of Biological Sciences, Dr. Harisingh Gour Central University, Sagar 470003, India.
authors: Siddhartha Kumar
authors: SK
authors: Mishra
authors: Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 406-840, Republic of Korea.
authors: Keun-Yeong
authors: KY
authors: Jeong
authors: Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 406-840, Republic of Korea.
authors: Poonam
authors: P
authors: Mander
authors: Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 406-840, Republic of Korea; Lee Gil Ya Cancer and Diabetes Institute, Department of Molecular Medicine, Gachon University, Inchon 406-840, Republic of Korea.
authors: Oh Byung
authors: OB
authors: Chul
authors: Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 406-840, Republic of Korea.
authors: Won-Sik
authors: WS
authors: Shim
authors: Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 406-840, Republic of Korea.
authors: Seung Hyun
authors: SH
authors: Oh
authors: Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 406-840, Republic of Korea.
authors: Ky-Youb
authors: KY
authors: Nam
authors: Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 406-840, Republic of Korea.
authors: Hwan Mook
authors: HM
authors: Kim
mesh_terms: D002118:Calcium / Q000378:metabolism*; D017610:Calcium Compounds / Q000494:pharmacology*; D002154:Calpain / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D007773:Lactates / Q000494:pharmacology*; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects
chemical_list: D017610:Calcium Compounds; D007773:Lactates; C110051:calcium lactate; D051416:Focal Adhesion Protein-Tyrosine Kinases; D002154:Calpain; D002118:Calcium
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