Endoplasmic reticulum stress confers 5-fluorouracil resistance in breast cancer cell via the GRP78/OCT4/lncRNA MIAT/AKT pathway.

5-Fluorouracil (5-FU) is an effective anticancer drug. However, high drug resistance limits its chemotherapeutic efficacy. Cancer cell resistance in colon cancer to 5-FU has been attributed to endoplasmic reticulum (ER) stress. But little is known about any similar role in resistance of breast cancer (BC). Here, we aim to investigate the role of ER stress played in BC cell resistance to 5-FU and to describe relevant molecular mechanisms. The expression patterns of 78-kDa glucose-regulated protein (GRP78), octamer 4 (OCT4), long non-coding RNA (lncRNA) myocardial infarction associated transcript (MIAT), and Protein kinase B (AKT) in BC MCF-7 cells resistant to 5-FU were determined by Western blot assay. Next, gain- and loss of-function experiments were conducted to verify effects of GRP78, OCT4, MIAT, and AKT on the to 5-FU sensitivity of MCF-7 cells and 5-FU resistant MCF cells (MCF-7/5-FU). Besides, the in vivo roles of the GRP78/OCT4/lncRNA MIAT/AKT pathway were assessed in tumor-bearing nude mice. 5-FU induced ER stress increased the expression of GRP78 in MCF-7 cells. GRP78 could positively regulate the expression of MIAT and AKT through upregulating OCT4, thereby contributing to 5-FU resistance in BC cells. Additionally, the function of GRP78 silencing in promoting tumor cell sensitivity was confirmed in vivo. These data supported an important role of the ER stress-mediated GRP78/OCT4/lncRNA MIAT/AKT pathway in BC cell resistance to 5-FU, highlighting potential molecular targets for combating 5-FU resistance in BC. AJCR