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LCL161 increases paclitaxel-induced apoptosis by degrading cIAP1 and cIAP2 in NSCLC
Chengcheng Yang1, Huangzhen Wang2,3, Boxiang Zhang2
1Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi, 710061, China.
Background:
LCL161, a novel Smac mimetic, is known to have anti-tumor activity and improve chemosensitivity in various cancers. However, the function and mechanisms of the combination of LCL161 and paclitaxel in non-small cell lung cancer (NSCLC) remain unknown.
Methods:
Cellular inhibitor of apoptotic protein 1 and 2 (cIAP1&2) expression in NSCLC tissues and adjacent non-tumor tissues were assessed by immunohistochemistry. The correlations between cIAP1&2 expression and clinicopathological characteristics, prognosis were analyzed. Cell viability and apoptosis were measured by MTT assays and Flow cytometry. Western blot and co-immunoprecipitation assay were performed to measure the protein expression and interaction in NF-kB pathway. siRNA-mediated gene silencing and caspases activity assays were applied to demonstrate the role and mechanisms of cIAP1&2 and RIP1 in lung cancer cell apoptosis. Mouse xenograft NSCLC models were used in vivo to determine the therapeutic efficacy of LCL161 alone or in combination with paclitaxel.
Results:
The expression of cIAP1 and cIAP2 in Non-small cell lung cancer (NSCLC) tumors was significantly higher than that in adjacent normal tissues. cIAP1 was highly expressed in patients with late TNM stage NSCLC and a poor prognosis. Positivity for both cIAP1 and cIAP2 was an independent prognostic factor that indicated a poorer prognosis in NSCLC patients. LCL161, an IAP inhibitor, cooperated with paclitaxel to reduce cell viability and induce apoptosis in NSCLC cells. Molecular studies revealed that paclitaxel increased TNFα expression, thereby leading to the recruitment of various factors and the formation of the TRADD-TRAF2-RIP1-cIAP complex. LCL161 degraded cIAP1&2 and released RIP1 from the complex. Subsequently, RIP1 was stabilized and bound to caspase-8 and FADD, thereby forming the caspase-8/RIP1/FADD complex, which activated caspase-8, caspase-3 and ultimately lead to apoptosis. In nude mouse xenograft experiments, the combination of LCL161 and paclitaxel degraded cIAP1,2, activated caspase-3 and inhibited tumor growth with few toxic effects.
Conclusion:
Thus, LCL161 could be a useful agent for the treatment of NSCLC in combination with paclitaxel.
Insights
The combination of LCL161 and paclitaxel effectively reduces non-small cell lung cancer (NSCLC) cell viability and induces apoptosis by targeting cellular inhibitor of apoptotic proteins (cIAP1&2). This approach shows promise for NSCLC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Smac mimetic LCL161 exhibits anti-tumor activity and enhances chemosensitivity in various cancers.
- The therapeutic potential and underlying mechanisms of combining LCL161 with paclitaxel in non-small cell lung cancer (NSCLC) are not well understood.
Purpose of the Study:
- To investigate the expression of cellular inhibitor of apoptotic protein 1 and 2 (cIAP1&2) in NSCLC.
- To elucidate the mechanisms by which LCL161 and paclitaxel combination therapy affects NSCLC cell apoptosis and tumor growth.
- To evaluate the therapeutic efficacy of LCL161 and paclitaxel in preclinical NSCLC models.
Main Methods:
- Immunohistochemistry to assess cIAP1&2 expression in NSCLC tissues.
- MTT assays and flow cytometry to measure cell viability and apoptosis.
- Western blot, co-immunoprecipitation, and siRNA to analyze the NF-kB pathway and protein interactions.
- In vivo studies using mouse xenograft models to evaluate therapeutic efficacy.
Main Results:
- cIAP1 and cIAP2 were significantly overexpressed in NSCLC tumors compared to normal tissues, with high cIAP1 expression correlating with advanced TNM stage and poor prognosis.
- The combination of LCL161 and paclitaxel significantly reduced NSCLC cell viability and induced apoptosis.
- Molecular analysis revealed that paclitaxel increased TNFα, leading to cIAP1&2 complex formation; LCL161 degraded cIAP1&2, releasing RIP1 to form a complex with FADD and caspase-8, activating downstream caspases and inducing apoptosis.
- In vivo studies demonstrated that the combination therapy inhibited tumor growth with minimal toxicity.
Conclusions:
- Elevated cIAP1&2 expression is associated with poor prognosis in NSCLC patients.
- LCL161 in combination with paclitaxel demonstrates significant anti-tumor activity in NSCLC by inducing apoptosis through the degradation of cIAP1&2 and activation of the caspase pathway.
- LCL161 represents a promising therapeutic agent for NSCLC treatment when combined with paclitaxel.
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