Pioglitazone inhibits EGFR/MDM2 signaling-mediated PPARγ degradation.
Aberrant activation of the epidermal growth factor receptor (EGFR) signaling is involved in many cancer events. Although peroxisome proliferator-activated receptor γ (PPARγ) has been implicated in inhibition of inflammation and cancer, EGFR/MDM2 signaling induces PPARγ phosphorylation and degradation. Here we found that cancer cells in response to EGF reduced PPARγ protein levels by inducing its phosphorylation, ubiquitination and degradation, but PPARγ agonist pioglitazone reversed this event. More importantly, pioglitazone increased cancer cell sensitivity to chemotherapy drugs. Therefore, our study revealed a novel mechanism that pioglitazone inhibited EGFR/MDM2-mediated cancer cell chemoresistance, which provides a novel strategy for cancer treatment.
Department of Oncology, The Affiliated Wujin Hospital, Jiangsu University, Changzhou, Jiangsu, People's Republic of China; Institute of Life Science, Jiangsu University, Zhenjiang, Jiangsu Province, People's Republic of China.
Juanjuan
J
Shi
Department of General Surgery, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.
Wenbo
W
Zhang
Institute of Life Science, Jiangsu University, Zhenjiang, Jiangsu Province, People's Republic of China.
Mengli
M
You
Institute of Life Science, Jiangsu University, Zhenjiang, Jiangsu Province, People's Republic of China.
Ying
Y
Xu
Institute of Life Science, Jiangsu University, Zhenjiang, Jiangsu Province, People's Republic of China.
Yongzhong
Y
Hou
Department of Oncology, The Affiliated Wujin Hospital, Jiangsu University, Changzhou, Jiangsu, People's Republic of China. Electronic address: jinjianhua19@126.com.
Jianhua
J
Jin
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D047495:PPAR gamma / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D000077205:Pioglitazone; D059748:Proteolysis / Q000187:drug effects*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D045162:Thiazolidinediones / Q000494:pharmacology*; D054875:Ubiquitination / Q000187:drug effects
D047495:PPAR gamma; D045162:Thiazolidinediones; D004815:Epidermal Growth Factor; D051736:Proto-Oncogene Proteins c-mdm2; D066246:ErbB Receptors; D000077205:Pioglitazone
Degradation; EGFR; PPARγ; Pioglitazone; Ubiquitination