Inhibition of mitogen-activated protein kinase signaling pathway sensitizes breast cancer cells to endoplasmic reticulum stress-induced apoptosis

Oncology Reports
Fen YangZhi Wen Jiang

Abstract

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) induces ER stress which is observed in many human diseases, including breast cancer. Cellular adaptation to ER stress is mediated by the unfolded protein response (UPR), which aims at restoring ER homeostasis. Higher levels of GRP78 expression indicates constitutive activation of the UPR in breast cancer leading to breast cancer cells that are relatively resistant to ER stress-induced apoptosis. Tunicamycin (TM), an ER stress inducer, constitutively activates the mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK), and (MEK)/ERK pathway which plays a role in upregulation of GRP78 by ER stress in that inhibition of MEK by U0126 reduces the levels of GRP78 and blocks its upregulation by TM. Inhibition of the MEK/ERK pathway by U0126 sensitizes breast cancer cells to TM-induced apoptosis. Inhibition of GRP78 by siRNA knockdown enhances TM- and U0126-induced apoptosis in breast cancer cells. This sensitization of breast cancer cells to TM-induced apoptosis by inhibition of MEK/ERK and GRP78 is caspase-dependent, at least in part, by activation of caspase-4. These results seem to indicate that GRP78 has potential as a chemotherapeutic...Continue Reading

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Citations

Oct 12, 2016·Journal of Agricultural and Food Chemistry·Xiaojuan LiuHang Xiao
May 2, 2017·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Jia-Teng ZhongZhi-Wei Feng
Oct 18, 2019·Frontiers in Oncology·Suraksha TamangAklank Jain
Mar 23, 2021·Mediators of Inflammation·Niti KumariBrian J North
Jun 18, 2021·Frontiers in Cell and Developmental Biology·Zhenyu NieShufang Zhang

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