Calcium channel TRPV6 promotes breast cancer metastasis by NFATC2IP

Xiang Xu; Na Li; Yugang Wang; Jinming Yu; Jun Mi

doi:10.1016/j.canlet.2021.07.017

Calcium channel TRPV6 promotes breast cancer metastasis by NFATC2IP

Cancer Lett. 2021 Oct 28:519:150-160. doi: 10.1016/j.canlet.2021.07.017. Epub 2021 Jul 13.

Authors

Xiang Xu¹, Na Li², Yugang Wang³, Jinming Yu⁴, Jun Mi⁵

Affiliations

¹ Basic Medical Institute, Hongqiao International Institute of Medicine, Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Department of Laboratory Medicine, Shanghai General Hospital Jiading Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Basic Medical Institute, Hongqiao International Institute of Medicine, Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
³ Department of Gastroenterology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: wang_yugang@sina.com.
⁴ Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Shandong, 250117, China. Electronic address: sdyujinming@163.com.
⁵ Basic Medical Institute, Hongqiao International Institute of Medicine, Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Department of Laboratory Medicine, Shanghai General Hospital Jiading Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: jmei@sjtu.edu.cn.

PMID: 34265397
DOI: 10.1016/j.canlet.2021.07.017

Abstract

Calcium channel TRPV6 upregulation is associated with poor prognosis of breast cancer by promoting invasion and metastasis, and TRPV6 is a potential target for breast cancer therapy. However, the mechanism by which TRPV6 promotes breast metastasis remains unclear. Here, we report that TRPV6 expression is upregulated in metastatic breast cancers and that TRPV6 overexpression or upregulation accelerates primary breast cancer cell migration. In contrast, TRPV6 suppression decreases cell migration. Mechanistically, TRPV6 activates NFATC2 by increasing NFATC2IP phosphorylation at Ser204, and CDK5 is a candidate kinase that may perform this phosphorylation. Consequently, activated NFATC2 increases breast cancer metastasis by upregulating ADAMTS6 expression. These observations suggest that TRPV6 increases NFATC2 transcriptional activity by increasing NFATC2IP phosphorylation, which consequently upregulates ADAMTS6 expression to promote breast cancer metastasis.

Keywords: Breast cancer; CDK5; Metastasis; NFATC2IP; TRPV6.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ADAMTS Proteins / metabolism
Animals
Breast Neoplasms / metabolism*
Breast Neoplasms / pathology
Calcium Channels / metabolism*
Carrier Proteins / metabolism*
Cell Line
Cell Line, Tumor
Cell Movement / physiology
Cyclin-Dependent Kinase 5 / metabolism
Female
HEK293 Cells
Humans
MCF-7 Cells
Mice
Phosphorylation / physiology
TRPV Cation Channels / metabolism*
Up-Regulation / physiology

Substances

Calcium Channels
Carrier Proteins
NFATC2IP protein, human
TRPV Cation Channels
TRPV6 protein, human
Cyclin-Dependent Kinase 5
ADAMTS Proteins