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 previou...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.展开更多
基金supported by grants from the National Natural Science Foundation of China(Grant No.81972163)the Guangdong Provincial Department of Science and Technology(Grant No.2019A1515010947)+3 种基金the State Key Lab of Respiratory Disease(Grant Nos.SKLRDQN201702,SKLRD-OP-202003)the Guangdong High Level University Clinical Cultivation Project(Grant No.2017-21020)the Wu Jieping Medical Foundation(Grant Nos.320.6750.18125,320.6750.19088-8)the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences(Grant No.2019PT320003)。
文摘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.
