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CEMIP upregulates BiP to promote breast cancer cell survival in hypoxia.

ABSTRACT: 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.

SUBMITTER: Banach A

PROVIDER: S-EPMC6611512 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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CEMIP upregulates BiP to promote breast cancer cell survival in hypoxia.

Banach Anna A Jiang Ya-Ping YP Roth Eric E Kuscu Cem C Cao Jian J Lin Richard Z RZ

Oncotarget 20190702 42

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 li ...[more]

PMID: 31303964

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Project description:In the hypoxic tumor microenvironment, cancer cells undergo metabolic reprogramming to survive. The present study aimed to assess the effects of hypoxic conditions on the lipid metabolism of breast cancer cells to elucidate the mechanisms by which cancer cells survive in an unfavorable environment. Cell viability was assessed by trypan blue staining, MTT and Annexin V-PI assays. Intracellular lipid levels were quantified using Nile red stain with immunofluorescence (IF). Autophagy was detected using LC3 antibody, Cyto-ID stain, IF, Western blotting, and flow cytometry. Fatty acid oxidation (FAO) and ATP production were analyzed using specific assays, while gene expression was assessed by reverse transcription-polymerase chain reaction. siRNA transfection was used for gene knockdown, and Kaplan-Meier analysis was performed for survival analysis. Fatostatin and rapamycin served as an inhibitor of sterol regulatory element-binding protein 1 (SREBP1) and an autophagy inducer, respectively. Under hypoxic conditions, triple-negative breast cancer (TNBC) MDA-MB-231 cells showed markedly increased survival and proliferation rates compared with normal cells (MCF-10A) and estrogen receptor-positive cells (MCF-7), with no change in apoptosis. Under hypoxic conditions, MDA-MB-231 cells showed increased expression of lipogenesis, autophagy and FAO-related enzymes and activation of SREBP1, a key transcription factor for lipogenic genes, whereas these changes were not observed in MCF-7 cells. When SREBP1 was inhibited with chemical inhibitors and siRNA, the expression of lipogenic, autophagic and FAO-related enzymes decreased, resulting in reduced ATP production and viability in hypoxic MDA-MB-231 cells; however, this effect was restored when an autophagy inducer was added. Kaplan-Meier analysis demonstrated that higher SREBP1 expression in patients with TNBC was associated with a worse prognosis, suggesting that SREBP1-mediated reprogramming of lipid metabolism and autophagy under hypoxia is essential for TNBC cell survival. The results of the present study indicate that strategies targeting SREBP1 could be exploited to treat TNBC and improve prognosis.

Dataset Information

CEMIP upregulates BiP to promote breast cancer cell survival in hypoxia.

Publications

CEMIP upregulates BiP to promote breast cancer cell survival in hypoxia.

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