CEMIP upregulates BiP to promote breast cancer cell survival in hypoxia
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Anna Banach1, Ya-Ping Jiang2, Eric Roth3, Cem Kuscu4, Jian Cao5 and Richard Z. Lin2,6
1 Molecular and Cellular Biology Program, Stony Brook University, Stony Brook, NY, USA
2 Department of Physiology and Biophysics, Institute of Molecular Cardiology, Stony Brook University, Stony Brook, NY, USA
3 Medical Scientist Training Program, Stony Brook University, Stony Brook, NY, USA
4 Transplant Research Institute, University of Tennessee Health Science Center, Memphis, TN, USA
5 Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, NY, USA
6 Medical Service, Northport Veterans Affairs Medical Center, Northport, NY, USA
|Richard Z. Lin,||email:||Richard.Lin@Stonybrook.edu|
Keywords: CEMIP; BiP; hypoxia; autophagy
Received: April 16, 2019 Accepted: May 26, 2019 Published: July 02, 2019
Cell migration-inducing protein (CEMIP) and binding immunoglobulin protein (BiP) are upregulated in human cancers, where they drive cancer progression and metastasis. It has been shown that CEMIP resides in the endoplasmic reticulum (ER) where it interacts with BiP to induce cell migration, but the relationship between the two proteins was previously unknown. Here we show that CEMIP mediates activation of the BiP promoter and upregulates BiP transcript and protein levels in breast cancer cell lines. Moreover, CEMIP overexpression confers protective adaptations to cancer cells under hypoxic conditions, by decreasing apoptosis, activating autophagy, and increasing glucose uptake, to facilitate tumor growth. We demonstrate that BiP signals downstream of CEMIP, modulating cellular resistance to hypoxia. Reducing BiP in CEMIP-expressing cells sensitized cells to hypoxia treatment, decreased glucose uptake, and resulted in tumor regression in vivo. Our study provides insights into the link between CEMIP and BiP expression and the pro-survival role they play in hypoxia. Better understanding of the mechanisms behind cancer cell adaptations to harsh tumor environments could lead to development of improved cancer treatments.
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