Inhibition of mitogen-activated protein kinase signaling pathway sensitizes breast cancer cells to endoplasmic reticulum stress-induced apoptosis
Inhibition of mitogen-activated protein kinase signaling pathway sensitizes breast cancer cells to endoplasmic reticulum stress-induced apoptosis
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丝裂原激活蛋白激酶信号通路的抑制使乳腺癌细胞对内质网应激诱导的细胞凋亡敏感
DOI：
10.3892/or.2016.4580
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发表时间：
2016-04-01
期刊：
影响因子：
4.2
通讯作者：
Jiang, Zhi Wen
中科院分区：
文献类型：
--
作者：
Yang, Fen;Tang, Xiao Yan;Jiang, Zhi Wen
内质网（ER）中未折叠蛋白的积累诱导内质网应激，这在包括乳腺癌在内的许多人类疾病中都观察到。细胞对内质网应激的适应是由未折叠蛋白反应（UPR）介导的，其目的是恢复内质网稳态。GRP78的高水平表达表明乳腺癌中UPR的组成性激活导致乳腺癌细胞相对抵抗内质网应激诱导的凋亡。Tunicamycin （TM）是一种内质网应激诱导剂，通过U0126抑制MEK，降低GRP78的水平，阻断TM对GRP78的上调，从而组成性地激活丝裂原活化蛋白激酶(MAPK)/细胞外信号调节激酶（ERK）和(MEK)/ERK通路，在内质网应激上调GRP78中发挥作用。U0126抑制MEK/ERK通路使乳腺癌细胞对tm诱导的凋亡敏感。siRNA敲低抑制GRP78可增强TM-和u0126诱导的乳腺癌细胞凋亡。通过抑制MEK/ERK和GRP78，乳腺癌细胞对tm诱导的凋亡的增敏作用至少部分依赖于caspase-4的激活。这些结果似乎表明GRP78具有作为化疗靶点的潜力，并对与MEK/ERK通路抑制剂诱导内质网应激的药物联合治疗乳腺癌的新治疗策略具有重要意义。
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)/extra-cellular 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 chemotherapeutical target and have important implications for new treatment strategies in breast cancer by combination with agents that induce ER stress with inhibitors of the MEK/ERK pathway.