Doxorubicin sensitizes cancer cells to Smac mimetic via synergistic activation of the CYLD/RIPK1/FADD/caspase-8-dependent apoptosis.
Chengkui YangQiao RanYifei ZhouShan LiuCong ZhaoXiaoliang YuFang ZhuYuting JiQian DuTao YangWei ZhangSudan HePublished in: Apoptosis : an international journal on programmed cell death (2021)
Smac/Diablo is a pro-apoptotic protein via interaction with inhibitors of apoptosis proteins (IAPs) to relieve their inhibition of caspases. Smac mimetic compounds (also known as antagonists of IAPs) mimic the function of Smac/Diablo and sensitize cancer cells to TNF-induced apoptosis. However, the majority of cancer cells are resistant to Smac mimetic alone. Doxorubicin is a widely used chemotherapeutic drug and causes adverse effect of cardiotoxicity in many patients. Therefore, it is important to find strategies of combined chemotherapy to increase chemosensitivity and reduce the adverse effects. Here, we report that doxorubicin synergizes with Smac mimetic to trigger TNF-mediated apoptosis, which is mechanistically distinct from doxorubicin-induced cell death. Doxorubicin sensitizes cancer cells including human pancreatic and colorectal cancer cells to Smac mimetic treatment. The combined treatment leads to synergistic induction of TNFα to initiate apoptosis through activating NF-κB and c-Jun signaling pathways. Knockdown of caspase-8 or knockout of FADD significantly blocked apoptosis synergistically induced by Smac mimetic and doxorubicin, but had no effect on cell death caused by doxorubicin alone. Moreover, Smac mimetic and doxorubicin-induced apoptosis requires receptor-interacting protein kinase 1 (RIPK1) and its deubiquitinating enzyme cylindromatosis (CYLD), not A20. These in vitro findings demonstrate that combination of Smac mimetic and doxorubicin synergistically triggers apoptosis through the TNF/CYLD/RIPK1/FADD/caspase-8 signaling pathway. Importantly, the combined treatment induced in vivo synergistic anti-tumor effects in the xenograft tumor model. Thus, the combined therapy using Smac mimetic and doxorubicin presents a promising apoptosis-inducing strategy with great potential for the development of anti-cancer therapy.
Keyphrases
- induced apoptosis
- endoplasmic reticulum stress
- cancer therapy
- cell death
- signaling pathway
- oxidative stress
- cell cycle arrest
- drug delivery
- pi k akt
- diabetic rats
- rheumatoid arthritis
- protein kinase
- epithelial mesenchymal transition
- emergency department
- end stage renal disease
- small molecule
- newly diagnosed
- chronic kidney disease
- cell proliferation
- immune response
- endothelial cells
- adverse drug
- peritoneal dialysis
- stem cells
- inflammatory response
- anti inflammatory
- nuclear factor
- mesenchymal stem cells
- toll like receptor
- protein protein