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乳酸钙对细胞内钙水平的调节通过钙依赖性钙蛋白酶影响结肠癌细胞的运动。

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

作者信息

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

机构信息

Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 406-840, Republic of Korea.

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.

出版信息

PLoS One. 2015 Jan 28;10(1):e0116984. doi: 10.1371/journal.pone.0116984. eCollection 2015.

DOI:10.1371/journal.pone.0116984
PMID:25629974
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4309579/
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.

摘要

癌细胞迁移是调节侵袭和转移的关键现象。黏着斑激酶（FAK）在各种癌症的细胞黏附和转移中起主要作用。饮食中补充钙与结肠癌之间的关系已得到广泛研究。然而，补充钙（Ca2+）对钙蛋白酶-FAK-迁移的影响尚不清楚。我们试图确定通过Ca2+结合乳酸（CaLa）裂解FAK的机制、其下游信号传导以及在人结肠癌细胞迁移中的作用。我们发现，用CaLa处理HCT116和HT-29细胞可立即长时间提高细胞内Ca2+（iCa2+）水平。Ca2+内流以剂量依赖方式诱导FAK裂解为N端FAK（FERM结构域）。磷酸化的FAK（p-FAK）也被裂解为其p-N端FAK。CaLa增加了结肠癌细胞的迁移能力。钙蛋白酶抑制剂钙肽素可逆转CaLa对两种癌细胞系中FAK和pFAK裂解的影响。裂解的FAK转位到细胞核中，并通过与MDM2相关的泛素化调节p53稳定性。CaLa诱导的Ca2+内流通过钙蛋白酶活性介导FAK和pFAK蛋白不稳定，从而增加结肠癌细胞的迁移能力。总之，这些结果表明，对于正在接受转移性癌症治疗的患者，在决定饮食中补充Ca2+时可能需要谨慎考虑。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50ea/4309579/1a25aed8fd02/pone.0116984.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50ea/4309579/c4367f7805ac/pone.0116984.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50ea/4309579/519427827c8e/pone.0116984.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50ea/4309579/9cb6b3a53e7b/pone.0116984.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50ea/4309579/b61063ea1fb3/pone.0116984.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50ea/4309579/8f9a45185c2c/pone.0116984.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50ea/4309579/2a5ab70f02d6/pone.0116984.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50ea/4309579/1a25aed8fd02/pone.0116984.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50ea/4309579/c4367f7805ac/pone.0116984.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50ea/4309579/519427827c8e/pone.0116984.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50ea/4309579/9cb6b3a53e7b/pone.0116984.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50ea/4309579/b61063ea1fb3/pone.0116984.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50ea/4309579/8f9a45185c2c/pone.0116984.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50ea/4309579/2a5ab70f02d6/pone.0116984.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50ea/4309579/1a25aed8fd02/pone.0116984.g007.jpg

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