A JNK-mediated autophagy pathway that triggers c-IAP degradation and necroptosis for anticancer chemotherapy.
A JNK-mediated autophagy pathway that triggers c-IAP degradation and necroptosis for anticancer chemotherapy.
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通过诱导细胞凋亡杀死癌细胞是化疗的主要机制之一。然而，许多癌细胞具有原发性或获得性凋亡抗性，导致化学抗性。在这项研究中，使用一种新的查耳酮衍生物查耳酮-24（Chal-24），我们通过自噬介导的坏死性凋亡（RIP 1和RIP 3依赖性坏死）确定了一种新的抗癌机制。Chal-24有效地杀死不同的癌细胞，诱导坏死的细胞形态，同时不引起可检测的半胱天冬酶激活。用necrostatin-1或通过敲低RIP 1和RIP 3阻断坏死性凋亡途径有效地阻断了Chal-24的细胞毒性，表明Chal-24诱导的细胞死亡与坏死性凋亡相关。Chal-24强烈激活JNK和ERK，阻断它们可有效抑制Chal-24诱导的细胞毒性。此外，Chal-24强烈诱导依赖于JNK介导的Bcl-2和Bcl-xL磷酸化以及Bcl-2或Bcl-xL从Beclin 1解离的自噬。重要的是，用药理学抑制剂或靶向必需的自噬组分ATG 7和Beclin 1的siRNA抑制自噬，有效地减弱了Chal-24诱导的细胞死亡。此外，我们发现自噬激活导致c-IAP 1和c-IAP 2降解和核糖体的形成，导致坏死性凋亡。因此，这些结果建立了一种新的机制，杀死癌细胞，涉及自噬介导的坏死性凋亡，这可能是用于克服化疗耐药性。
Killing cancer cells through the induction of apoptosis is one of the main mechanisms of chemotherapy. However, numerous cancer cells have primary or acquired apoptosis resistance, resulting in chemoresistance. In this study, using a novel chalcone derivative chalcone-24 (Chal-24), we identified a novel anticancer mechanism through autophagy-mediated necroptosis (RIP1- and RIP3-dependent necrosis). Chal-24 potently killed different cancer cells with induction of necrotic cellular morphology while causing no detectable caspase activation. Blocking the necroptosis pathway with either necrostatin-1 or by knockdown of RIP1 and RIP3 effectively blocked the cytotoxicity of Chal-24, suggesting that Chal-24-induced cell death is associated with necroptosis. Chal-24 robustly activated JNK and ERK and blockage of which effectively suppressed Chal-24-induced cytotoxicity. In addition, Chal-24 strongly induced autophagy that is dependent on JNK-mediated phosphorylation of Bcl-2 and Bcl-xL and dissociation of Bcl-2 or Bcl-xL from Beclin1. Importantly, suppression of autophagy, with either pharmacological inhibitors or siRNAs targeting the essential autophagy components ATG7 and Beclin1, effectively attenuated Chal-24-induced cell death. Furthermore, we found that autophagy activation resulted in c-IAP1 and c-IAP2 degradation and formation of the Ripoptosome that contributes to necroptosis. These results thus establish a novel mechanism for killing cancer cells that involves autophagy-mediated necroptosis, which may be employed for overcoming chemoresistance.
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