Inactivation of tumor suppressor gene Clusterin leads to hyperactivation of TAK1-NF-κB signaling axis in lung cancer cells and denotes a therapeutic opportunity
机构：[1]Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.[2]Clinical Research Center, the Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China.[3]Department of Pathology, Zhejiang, Provincial People’s Hospital, People’s Hospital of Hangzhou, Medical College, Hangzhou 310014, Zhejiang Province, China.[4]Beijing Tongren Hospital, Capital Medical University, 100730 Beijing, China.首都医科大学附属北京同仁医院首都医科大学附属同仁医院
Purpose: Clinical success of precision medicine is severely limited by de novo or acquired drug resistance. It remains a clinically unmet need to treat these patients. Tumor suppressor genes (TSGs) play a critical role in tumorigenesis and impact the therapeutic effect of various treatments. Experimental Design: Using clinical data, in vitro cell line data and in vivo mouse model data, we revealed the tumor suppressive role of Clusterin in lung cancer. We also delineated the signaling cascade elicited by loss of function of CLU in NSCLC cells and tested precision medicine for CLU deficient lung cancers. Results: CLU is a potent and clinically relevant TSG in lung cancer. Mechanistically, CLU inhibits TGFBR1 to recruit TRAF6/TAB2/TAK1 complex and thus inhibits activation of TAK1-NF-kappa B signaling axis. Lung cancer cells with loss of function of CLU show exquisite sensitivity to TAK1 inhibitors. Importantly, we show that a significant portion of Kras mutation positive NSCLC patients are concurrently deficient of CLU and that TAK1 kinase inhibitor synergizes with existing drugs to treat this portion of lung cancers patients. Conclusions: Combinational treatment with TAK1 inhibitor and MEK1/2 inhibitor effectively shrank Kras mutation positive and CLU deficient NSCLC tumors. Moreover, we put forward a concept that loss of function of a TSG rewires signaling network and thereby creates an Achilles' heel in tumor cells which could be exploited in precision medicine.
基金：
NSFC
(81972778; 81672309), Guangzhou Research Project of
Science and Technology for Citizen Health
(201803010124), the Fundamental Research Funds for
the Central Universities (21619101), and the Science
and Technology Program of Guangzhou
(201604020162), Science and Technology Program of
Guangdong (2017B020227001).
第一作者机构：[1]Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Zhipeng Chen,Zhenzhen Fan,Xiaowei Dou,et al.Inactivation of tumor suppressor gene Clusterin leads to hyperactivation of TAK1-NF-κB signaling axis in lung cancer cells and denotes a therapeutic opportunity[J].THERANOSTICS.2020,10(25):11520-11534.doi:10.7150/thno.44829.
APA：
Zhipeng Chen,Zhenzhen Fan,Xiaowei Dou,Qian Zhou,Guandi Zeng...&Liang Chen.(2020).Inactivation of tumor suppressor gene Clusterin leads to hyperactivation of TAK1-NF-κB signaling axis in lung cancer cells and denotes a therapeutic opportunity.THERANOSTICS,10,(25)
MLA：
Zhipeng Chen,et al."Inactivation of tumor suppressor gene Clusterin leads to hyperactivation of TAK1-NF-κB signaling axis in lung cancer cells and denotes a therapeutic opportunity".THERANOSTICS 10..25(2020):11520-11534
医学