FGFR/RACK1 interacts with MDM2, promotes P53 degradation, and inhibits cell senescence in lung squamous cell carcinoma

• 作者: Tao Chen Fei Wang Shupei Wei Yingjie Nie Xiaotao Zheng Yu Deng Xubin Zhu Yuezhen Deng Nanshan Zhong Chengzhi Zhou
• 来源期刊: 癌症生物学与医学（英文版）
• 年，卷（期）: 2021,（3）
• 所属期刊栏目: ORIGINAL ARTICLE
• 页码范围: 665-674
• 页数: 10页
• 语种: 英文
• DOI: 10.20892/j.issn.2095-3941.2020.0389

摘要

Objective: FGFR is considered an important driver gene of lung squamous cell carcinoma (LSCC). Thus, identification of the biological events downstream of FGFR is important for the treatment of this malignancy. Our previous study has shown that the FGFR/RACK1 complex interacts with PKM2 and consequently promotes glycolysis in LSCC cells. However, the biological functions of the FGFR/RACK1 complex remain poorly understood. Methods: Anchorage-independent assays and in vivo tumorigenesis assays were performed to evaluate cancer cell malignancy. Distant seeding assays were performed to evaluate cancer cell metastasis. β-gal staining was used to examine cell senescence, and immunoprecipitation assays were performed to examine the interactions among FGFR, RACK1, and MDM2. Results: FGFR/RACK1 was found to regulate the senescence of LSCC cells. Treatment with PD166866, an inhibitor of FGFR, or knockdown of RACK1 induced senescence in LSCC cells (P < 0.01). A molecular mechanistic study showed that FGFR/RACK1/MDM2 form a complex that promotes the degradation of p53 and thus inhibits cell senescence. PD166866 and RG7112, an MDM2/p53 inhibitor, cooperatively inhibited the colony formation and distal seeding of LSCC cells (P < 0.01), and upregulated the expression of p53 and p21. Conclusions: Together, our findings revealed the regulatory roles and mechanisms of FGFR/RACK1 in cell senescence. This understanding should be important in the treatment of LSCC.