Downregulation of hPMC2 imparts chemotherapeutic sensitivity to alkylating agents in breast cancer cells.
Downregulation of hPMC2 imparts chemotherapeutic sensitivity to alkylating agents in breast cancer cells.
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hPMC2 的下调赋予乳腺癌细胞对烷化剂的化疗敏感性。
DOI：
10.1080/15384047.2015.1016661
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发表时间：
2015
影响因子：
3.6
通讯作者：
Montano,MonicaM
中科院分区：
文献类型：
--
作者：
Krishnamurthy,Nirmala;Liu,Lili;Xiong,Xiahui;Zhang,Junran;Montano,MonicaM
据报道，三阴性乳腺癌细胞系对替莫唑胺 (TMZ) 的细胞毒性作用具有抵抗力。我们之前已经证明，一种新的蛋白质，人类爪蟾基因的同源物，预防有丝分裂灾难（hPMC2）在雌激素诱导的无碱基位点的修复中发挥作用。我们目前的研究提供了证据，表明用替莫唑胺 (TMZ) 处理的 MDA-MB-231 和 MDA-MB-468 乳腺癌细胞中 hPMC2 的下调会降低细胞存活率。这种对 TMZ 敏感性的增加与 DNA 中无嘌呤/无嘧啶 (AP) 位点数量的增加有关。我们还表明，用另一种烷化剂 BCNU 处理会导致 AP 位点增加和细胞存活率降低。蛋白质印迹分析和免疫荧光实验的定量表明，用 TMZ 处理 hPMC2 下调细胞会导致 γ-H2AX 水平增加，表明双链 DNA 断裂增加。彗星试验还揭示了 hPCM2 下调后 TMZ 处理的细胞中 DNA 双链断裂的增强。总的来说，我们提供的证据表明乳腺癌细胞中 hPMC2 的下调会增加烷化剂的细胞毒性，代表了乳腺癌治疗的一种新机制。因此，我们的数据对乳腺癌的治疗具有重要的临床意义，并带来了潜在的新治疗策略。
Triple negative breast cancer cell lines have been reported to be resistant to the cyotoxic effects of temozolomide (TMZ). We have shown previously that a novel protein, human homolog of Xenopus gene which Prevents Mitotic Catastrophe (hPMC2) has a role in the repair of estrogen-induced abasic sites. Our present study provides evidence that downregulation of hPMC2 in MDA-MB-231 and MDA-MB-468 breast cancer cells treated with temozolomide (TMZ) decreases cell survival. This increased sensitivity to TMZ is associated with an increase in number of apurinic/apyrimidinic (AP) sites in the DNA. We also show that treatment with another alkylating agent, BCNU, results in an increase in AP sites and decrease in cell survival. Quantification of western blot analyses and immunofluorescence experiments reveal that treatment of hPMC2 downregulated cells with TMZ results in an increase in γ-H2AX levels, suggesting an increase in double strand DNA breaks. The enhancement of DNA double strand breaks in TMZ treated cells upon downregulation of hPCM2 is also revealed by the comet assay. Overall, we provide evidence that downregulation of hPMC2 in breast cancer cells increases cytotoxicity of alkylating agents, representing a novel mechanism of treatment for breast cancer. Our data thus has important clinical implications in the management of breast cancer and brings forth potentially new therapeutic strategies.