PKC is an indispensable factor in promoting environmental toxin chromium-mediated transformation and drug resistance.
PKC is an indispensable factor in promoting environmental toxin chromium-mediated transformation and drug resistance.
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DOI：
10.18632/aging.203917
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发表时间：
2022-02-24
期刊：
影响因子：
--
通讯作者：
Chen C
中科院分区：
文献类型：
--
作者：
Ganapathy S;Liu J;Yu T;Xiong R;Zhang Q;Makriyannis A;Chen C
六价铬[Cr（VI）]污染是一个严重的环境问题，这不仅是由于其毒性，而且还由于其致癌性。虽然研究揭示了Cr（VI）诱导的致癌作用的几个特征，但Cr（VI）如何协调多种促有丝分裂途径以促进肿瘤发生和进展的潜在机制仍未完全了解。Src/Ras和其他生长相关途径被证明是Cr（VI）引发的肿瘤倾向行动的关键球员。蛋白激酶C（PKC，一种重要的信号转导子）在Cr（VI）介导的致癌作用中的作用尚未得到深入研究。在这项研究中，使用人支气管/肺上皮细胞和角质形成细胞，我们表明，PKC活性增加的瞬时或慢性铬（VI）曝光，这起不到作用，激活Src/Ras信号和ROS上调这种金属毒素。慢性Cr（VI）处理的细胞中的PKC稳定Bcl-2，以减轻阿霉素（一种抗癌药物）介导的细胞凋亡。在用PKC抑制剂GO 6976抑制该激酶后，慢性暴露于Cr（VI）的细胞部分恢复对阿霉素的敏感性。然而，当共抑制PKC和Ras时，慢性Cr（VI）处理的细胞对阿霉素完全响应并且不能被转化。两者合计，我们的研究提供了一个新的见解的机制，其中PKC是一个不可或缺的球员，并与其他促有丝分裂途径合作，以实现铬（VI）诱导的致癌作用，以及建立耐药性。这些数据还表明，活性PKC可以作为一个潜在的生物标志物，用于早期检测的健康损害的Cr（VI）和治疗目标，为开发新的治疗方法所引起的疾病的Cr（VI）。
Hexavalent chromium [Cr(VI)] pollution is a serious environmental problem, due to not only its toxicity but also carcinogenesis. Although studies reveal several features of Cr(VI)-induced carcinogenesis, the underlying mechanisms of how Cr(VI) orchestrates multiple mitogenic pathways to promote tumor initiation and progression remain not fully understood. Src/Ras and other growth-related pathways are shown to be key players in Cr(VI)-initiated tumor prone actions. The role of protein kinase C (PKC, an important signal transducer) in Cr(VI)-mediated carcinogenesis has not been thoroughly investigated. In this study, using human bronchial/lung epithelial cells and keratinocytes, we demonstrate that PKC activity is increased by transient or chronic Cr(VI) exposure, which plays no role in the activation of Src/Ras signaling and ROS upregulation by this metal toxin. PKC in chronic Cr(VI)-treated cells stabilizes Bcl-2 to mitigate doxorubicin (an anti-cancer drug)-mediated apoptosis. After the suppression of this kinase by GO6976 (a PKC inhibitor), the cells chronically exposed to Cr(VI) partially regain the sensitivity to doxorubicin. However, when co-suppressed PKC and Ras, the chronic Cr(VI)-treated cells become fully responsive to doxorubicin and are unable to be transformed. Taken together, our study provides a new insight into the mechanisms, in which PKC is an indispensable player and cooperates with other mitogenic pathways to achieve Cr(VI)-induced carcinogenesis as well as to establish drug resistance. The data also suggest that active PKC can serve as a potential biomarker for early detection of health damages by Cr(VI) and therapeutic target for developing new treatments for diseases caused by Cr(VI).
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影响因子：
4.8
作者：
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DOI：
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发表时间：
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影响因子：
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