Department of Experimental and Diagnostic Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation (ICSI), Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
Cell Cycle. 2012 Mar 1;11(5):1040-8. doi: 10.4161/cc.11.5.19520.
The atypical protein kinase C (PKC) isoform zeta (PKCζ) has been implicated in the intracellular transduction of mitogenic and apoptotic signals by acting on different signaling pathways. The key role of these processes in tumorigenesis suggests a possible involvement of PKCζ in this event. PKCζ is activated by cytotoxic treatments, inhibits apoptotic cell death and reduces the sensitivity of cancer cells to chemotherapeutic agents. Here, using pharmacological and DNA recombinant approaches, we show that oxidative stress triggers nuclear translocation of PKCζ and induces resistance to apoptotic agents. Accordingly, chemoresistant cells show accumulation of PKCζ within the nucleus, and a nuclear-targeted PKCζ transfected in tumor cells decreases sensitivity to apoptosis. We thus developed a novel recombinant protein capable of selectively inhibiting the nuclear fraction of PKCζ that restored the susceptibility to apoptosis in cells in which PKCζ was enriched in the nuclear fraction, including chemoresistant cells. These findings establish the importance of PKCζ as a possible target to increase the effectiveness of anticancer therapies and highlight potential sites of intervention.
非典型蛋白激酶 C（PKC）同工型 ζ（PKCζ）通过作用于不同的信号通路，参与有丝分裂和细胞凋亡信号的细胞内转导。这些过程在肿瘤发生中的关键作用表明 PKCζ 可能参与了这一事件。PKCζ 被细胞毒性治疗激活，抑制细胞凋亡死亡并降低癌细胞对化疗药物的敏感性。在这里，我们使用药理学和 DNA 重组方法表明，氧化应激触发 PKCζ 的核转位，并诱导对凋亡剂的抗性。因此，耐药细胞显示 PKCζ 在核内积累，并且核靶向 PKCζ 转染的肿瘤细胞降低了对细胞凋亡的敏感性。因此，我们开发了一种新型重组蛋白，能够选择性抑制 PKCζ 的核部分，恢复了 PKCζ 在富含核部分的细胞（包括耐药细胞）中的易感性。这些发现确立了 PKCζ 作为增加抗癌疗法有效性的可能靶标的重要性，并强调了潜在的干预部位。
