FoxO3a confers cetuximab resistance in RAS wild-type metastatic colorectal cancer through c-Myc.
Resistance to epidermal growth factor receptor (EGFR) targeted monoclonal antibody therapy represents a clinical challenge in patients suffered from RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, the molecular mechanisms and key factors conferring this resistance are largely unknown. Forkhead transcription factors of the O class 3a (FoxO3a), an important regulator of cell survival, has been reported with dual functions in tumor recently. In this study, we found that FoxO3a was highly expressed in cetuximab resistant CRC tissues compared with cetuximab sensitive tissues. We therefore further analyzed its function in induced cetuximab resistant RAS-WT CRC cells (Caco2-CR) and intrinsic resistant cells with BRAF mutation (HT29). We found that FoxO3a was significantly up-regulated in Caco2-CR as well as in cetuximab treated HT29 cells. Knockdown of FoxO3a could sensitize these cells to cetuximab treatment with reduced cell proliferation and migration ability. Further, biochemical experiments demonstrated that FoxO3a directly bind to c-Myc promoter and activated the transcription of the c-Myc gene, thus participated in regulating of c-Myc downstream genes, including ACO2, LARS2, MRPL12 and PKM2 in these resistant cells. Moreover, knockdown of c-Myc elevated cell apoptosis to cetuximab treatment and suppressed cell proliferation and migration ability consistently. Altogether, our study indicates that FoxO3a might be a key regulator in cetuximab resistance through up-regulating c-Myc in colorectal cancer targeted therapy.
Department of Medical Oncology, Zhong Shan Hospital, Fu Dan University, Shanghai, China.
Yiyi
Y
Yu
Department of Medical Oncology, Zhong Shan Hospital, Fu Dan University, Shanghai, China.
Mengzhou
M
Guo
Department of General Surgery, Zhong Shan Hospital, Fu Dan University, Shanghai, China.
Ye
Y
Wei
Department of Medical Oncology, Zhong Shan Hospital, Fu Dan University, Shanghai, China.
Shan
S
Yu
Department of Medical Oncology, Zhong Shan Hospital, Fu Dan University, Shanghai, China.
Hong
H
Li
Department of Medical Oncology, Zhong Shan Hospital, Fu Dan University, Shanghai, China.
Yan
Y
Wang
Department of Medical Oncology, Zhong Shan Hospital, Fu Dan University, Shanghai, China.
Xiaojing
X
Xu
Department of Medical Oncology, Zhong Shan Hospital, Fu Dan University, Shanghai, China.
Yuehong
Y
Cui
Department of Medical Oncology, Zhong Shan Hospital, Fu Dan University, Shanghai, China.
Jiawen
J
Tian
Department of Medical Oncology, Zhong Shan Hospital, Fu Dan University, Shanghai, China.
Li
L
Liang
Department of Medical Oncology, Zhong Shan Hospital, Fu Dan University, Shanghai, China.
Ke
K
Peng
Department of Medical Oncology, Zhong Shan Hospital, Fu Dan University, Shanghai, China.
Tianshu
T
Liu
D000818:Animals; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D018938:Caco-2 Cells; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D019073:HT29 Cells; D006801:Humans; D008819:Mice, Nude; D009154:Mutation; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects
D000074322:Antineoplastic Agents, Immunological; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000068818:Cetuximab
FoxO3a; RAS; c-Myc; cetuximab resistance; colorectal cancer