Cisplatin-induced senescence in ovarian cancer cells is mediated by GRP78
Cisplatin-induced senescence in ovarian cancer cells is mediated by GRP78
复制标题
顺铂诱导的卵巢癌细胞衰老是由 GRP78 介导的。
DOI：
10.3892/or.2014.3147
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发表时间：
2014-06-01
期刊：
影响因子：
4.2
通讯作者：
Wang, Hui
中科院分区：
文献类型：
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作者：
Li, Wei;Wang, Wei;Wang, Hui
葡萄糖调节蛋白78（GRP78）是最丰富且特征明确的葡萄糖调节蛋白，是一种主要的应激诱导型分子伴侣，定位于内质网（ER）。本研究的目的是探讨GRP78参与卵巢癌细胞对顺铂衰老敏感性的机制。在本研究中，我们发现对化疗敏感的卵巢肿瘤切片对异染色质蛋白1 - γ（HP1 - γ）呈强染色，但对GRP78呈弱染色。与顺铂耐药的C13K细胞相比，GRP78低表达的顺铂敏感的A2780细胞在顺铂剂量梯度暴露后更容易发生衰老。GRP78的强制过表达通过P53和细胞分裂周期蛋白2（CDC2）保护顺铂敏感的A2780细胞免受顺铂诱导的衰老。GRP78的敲低通过P21和CDC2恢复了顺铂耐药的C13K细胞对顺铂的衰老敏感性。已证实GRP78对内质网钙库中Ca²⁺释放的调控与卵巢癌细胞系中顺铂诱导衰老的敏感性有关。总之，GRP78可能通过多种机制对卵巢癌细胞具有抗衰老作用。针对GRP78的干预可能会降低卵巢癌的顺铂耐药性。
Glucose-regulated protein 78 (GRP78), the most abundant and well-characterized glucose-regulated protein, is a major stress-inducible chaperone localized to the endoplasmic reticulum (ER). The purpose of the present study was to investigate the mechanisms of GRP78 involved in the senescence sensitivity of ovarian cancer cells to cisplatin. In the present study, we found that the chemotherapy-sensitive ovarian tumor sections showed strong staining for heterochromatin protein 1-γ (HP1-γ), but weak staining for GRP78. Cisplatin-sensitive A2780 cells with low expression of GRP78 tended to undergo senescence easily when compared with the cisplatin-resistant C13K cells following a dose-gradient cisplatin exposure. Forced overexpression of GRP78 protected the cisplatin-sensitive A2780 cells from cisplatin-induced senescence through P53 and CDC2. Knockdown of GRP78 rescued the senescence sensitivity of cisplatin-resistant C13K cells to cisplatin through P21 and CDC2. Twisting of Ca2+ release from ER stores by GRP78 was established to be associated with the sensitivity of cisplatin-induced senescence in ovarian cancer cell lines. In conclusion, GRP78 may have anti-senescence effects on ovarian cancer cells involving multiple mechanisms. Intervention against GRP78 may reduce cisplatin resistance in ovarian cancer.