Wang Jinjing, Guo Wenhao, Zhou Hang, Luo Na, Nie Chunlai, Zhao Xinyu, Yuan Zhu, Liu Xinyu, Wei Yuquan
Department of Abdominal Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, P. R. China.
Department of Chemotherapy, Sichuan Cancer Hospital, Chengdu, Sichuan 610041, P. R. China.
Oncotarget. 2015 Jul 10;6(19):17192-205. doi: 10.18632/oncotarget.3780.
Chemoresistance in cancer has previously been attributed to gene mutations or deficiency. Caspase mutations or Bax deficiency can lead to resistance to cancer drugs. We recently demonstrated that Bak initiates a caspase/Bax-independent cell death pathway. We show that Plumbagin (PL) (5-hydroxy-2-methyl-1,4-napthoquinone), a medicinal plant-derived naphthoquinone that is known to have anti-tumor activity in a variety of models, induces caspase-independent cell death in HCT116 Bax knockout (KO) or MCF-7 Bax knockdown (KD) cells that express wild-type (WT) Bak. The re-expression of Bax in HCT116 Bax KO cells fails to enhance the PL-induced cell death. Additionally, Bak knockdown by shRNA efficiently attenuates PL-induced cell death. These results suggest that PL-induced cell death depends primarily on Bak, not Bax, in these cells. Further experimentation demonstrated that p53 Ser15 phosphorylation and mitochondrial translocation mediated Bak activation and subsequent cell death. Knockdown of p53 or a p53 Ser15 mutant significantly inhibited p53 mitochondrial translocation and cell death. Furthermore, we found that Akt mediated p53 phosphorylation and the subsequent mitochondrial accumulation. Taken together, our data elaborate the role of Bak in caspase/Bax-independent cell death and suggest that PL may be an effective agent for overcoming chemoresistance in cancer cells with dysfunctional caspases.
癌症中的化学抗性以前被归因于基因突变或缺陷。半胱天冬酶突变或Bax缺陷可导致对癌症药物的抗性。我们最近证明，Bak启动了一条不依赖半胱天冬酶/Bax的细胞死亡途径。我们发现，白花丹素（PL）（5-羟基-2-甲基-1,4-萘醌），一种源自药用植物的萘醌，已知在多种模型中具有抗肿瘤活性，可在表达野生型（WT）Bak的HCT116 Bax基因敲除（KO）或MCF-7 Bax基因敲低（KD）细胞中诱导不依赖半胱天冬酶的细胞死亡。在HCT116 Bax KO细胞中重新表达Bax未能增强PL诱导的细胞死亡。此外，通过shRNA敲低Bak可有效减弱PL诱导的细胞死亡。这些结果表明，在这些细胞中，PL诱导的细胞死亡主要依赖于Bak，而非Bax。进一步的实验表明，p53丝氨酸15磷酸化和线粒体易位介导了Bak的激活及随后的细胞死亡。敲低p53或p53丝氨酸15突变体可显著抑制p53的线粒体易位和细胞死亡。此外，我们发现Akt介导了p53的磷酸化及随后的线粒体积累。综上所述，我们的数据阐述了Bak在不依赖半胱天冬酶/Bax的细胞死亡中的作用，并表明PL可能是克服半胱天冬酶功能失调的癌细胞化学抗性的有效药物。
