Suppression of PKC causes oncogenic stress for triggering apoptosis in cancer cells.
Suppression of PKC causes oncogenic stress for triggering apoptosis in cancer cells.
复制标题
DOI：
10.18632/oncotarget.16047
复制
发表时间：
2017-05-09
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;Peng B;Shen L;Yu T;Lafontant J;Li P;Xiong R;Makriyannis A;Chen C
超过 30% 的人类恶性肿瘤，尤其是 90% 的胰腺癌中都会出现 ras 功能突变。突变体 ras 通过激活多种效应通路，不仅促进细胞生长或存活，还促进细胞凋亡，具体取决于细胞类型或环境。为了进一步研究致癌ras诱导细胞凋亡的机制，我们利用ras环突变基因，证明Akt在人胰腺癌或异位表达突变K-ras的HPNE细胞中在Ras下游发挥作用，在同时抑制PKCα和β后诱导细胞凋亡。在此凋亡过程中，胰腺癌细胞和前列腺癌 DU145 细胞中的氧化还原机制异常开启。 p73 被磷酸化并转位至细胞核，伴随着 UPR 激活并诱导细胞凋亡。体外结果得到体内数据的证实。因此，我们的研究表明 PKC α 和 β 似乎与致癌 Ras 或突变的 Akt 应对，以维持癌细胞内稳态的平衡。一旦这些 PKC 同工型被抑制，癌细胞中的氧化还原状态就会被破坏，从而引发持续的致癌应激和随后的细胞凋亡危机。
Gain of functional mutations in ras occurs in more than 30% of human malignancies and in particular 90% of pancreatic cancer. Mutant ras, via activating multiple effector pathways, not only promote cell growth or survival, but also apoptosis, depending upon cell types or circumstances. In order to further study the mechanisms of apoptosis induced by oncogenic ras, we employed the ras loop mutant genes and demonstrated that Akt functioned downstream of Ras in human pancreatic cancer or HPNE cells ectopically expressing mutated K-ras for the induction of apoptosis after the concurrent suppression of PKC α and β. In this apoptotic process, the redox machinery was aberrantly switched on in the pancreatic cancer cells as well as prostate cancer DU145 cells. p73 was phosphorylated and translocated to the nucleus, accompanied with UPR activation and induction of apoptosis. The in vitro results were corroborated by the in vivo data. Thus, our study indicated that PKC α and β appeared coping with oncogenic Ras or mutated Akt to maintain the balance of the homeostasis in cancer cells. Once these PKC isoforms were suppressed, the redox state in the cancer cells was disrupted, which elicited persistent oncogenic stress and subsequent apoptotic crisis.
影响因子：
4
作者：
Guo, Jinjin;Zhu, Tongbo;Luo, Ling-Yu;Huang, Yi;Sunkavalli, Raja G.;Chen, Chang Yan
通讯作者：
Chen, Chang Yan