Zurgil Udi, Ben-Ari Assaf, Rotem-Dai Noa, Karp Galia, Krasnitsky Ella, Frost Sigal A, Livneh Etta
*Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
Biochem Soc Trans. 2014 Dec;42(6):1519-23. doi: 10.1042/BST20140182.
The successful treatment of cancer in a disseminated stage using chemotherapy is limited by the occurrence of drug resistance, often mediated by anti-apoptotic mechanisms. Thus the challenge is to pinpoint the underlying key factors and to develop therapies for their direct targeting. Protein kinase C (PKC) enzymes are promising candidates, as some PKCs were shown to be involved in regulation of apoptosis. Our studies and others have shown that PKCη is an anti-apoptotic kinase, able to confer protection on tumour cells against stress and chemotherapy. We have demonstrated that PKCη shuttles between the cytoplasm and the nucleus and that upon DNA damage is tethered at the nuclear membrane. The C1b domain mediates translocation of PKCη to the nuclear envelope and, similar to the full-length protein, could also confer protection against cell death. Furthermore, its localization in cell and nuclear membranes in breast cancer biopsies of neoadjuvant-treated breast cancer patients was an indicator for poor survival and a predictor for the effectiveness of treatment. PKCη is also a novel biomarker for poor prognosis in non-small-cell lung cancer (NSCLC). Thus PKCη presents a potential target for therapy where inhibition of its activity and/or translocation to membranes could interfere with the resistance to chemotherapy.
使用化疗成功治疗播散期癌症受到耐药性的限制，耐药性通常由抗凋亡机制介导。因此，挑战在于找出潜在的关键因素，并开发针对这些因素的直接靶向疗法。蛋白激酶C（PKC）酶是很有前景的候选对象，因为一些PKC已被证明参与细胞凋亡的调控。我们和其他研究表明，PKCη是一种抗凋亡激酶，能够保护肿瘤细胞免受应激和化疗的影响。我们已经证明，PKCη在细胞质和细胞核之间穿梭，并且在DNA损伤时会被束缚在核膜上。C1b结构域介导PKCη向核膜的转运，并且与全长蛋白相似，也能赋予细胞对死亡的保护作用。此外，在接受新辅助治疗的乳腺癌患者的活检组织中，其在细胞膜和核膜上的定位是生存不良的指标以及治疗效果的预测指标。PKCη也是非小细胞肺癌（NSCLC）预后不良的新型生物标志物。因此，PKCη是一个潜在的治疗靶点，抑制其活性和/或向膜的转运可能会干扰对化疗的耐药性。
