Cheng-Yi Wang1, Ting-Ting Chao2, Fang-Yu Chang2, Yen-Lin Chen3, Yi-Ting Tsai2, Hen-I Lin4, Yuh-Chin T Huang5, Chung-Wai Shiau6, Chong-Jen Yu7, Kuen-Feng Chen8. 1. Department of Internal Medicine, Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City 23148, Taiwan; Medical Research Center, Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City 23148, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 10002, Taiwan. 2. Medical Research Center, Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City 23148, Taiwan. 3. Department of Pathology, Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City 23148, Taiwan. 4. Department of Internal Medicine, Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City 23148, Taiwan. 5. Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States. 6. Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 11221, Taiwan. 7. Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University, Taipei 10002, Taiwan. Electronic address: jefferycjyu@ntu.edu.tw. 8. Department of Medical Research, National Taiwan University Hospital, Taipei 10002, Taiwan; National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei 10002, Taiwan. Electronic address: kfchen1970@ntu.edu.tw.
Abstract
BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors show favorable clinical response in some patients with non-small cell lung cancer (NSCLC) who have no EGFR mutation, indicating alternative mechanisms for their tumoricidal effects. We previously showed erlotinib, a selective EGFR antagonist, inhibited the growth of sensitive hepatocellular carcinoma cells by inhibiting the cancerous inhibitor of protein phosphatase 2A (CIP2A) pathway. The aim of this study was to determine if erlotinib can also inhibit the growth of NSCLC cells by inactivating the CIP2A-dependent signaling pathway. METHODS: Four NSCLC cell lines (H358 H441 H460 and A549) were treated with erlotinib to determine their sensitivity to erlotinib-induced cell death and apoptosis. Expression of CIP2A and the downstream AKT were analyzed. The effects of CIP2A on erlotinib-induced apoptosis were confirmed by overexpression of CIP2A and knockdown of CIP2A gene expression in the sensitive cells and resistant cells, respectively. In vivo efficacy of erlotinib against H358 xenograft tumor was also determined in nude mice. RESULTS: Erlotinib induced significant cell death and apoptosis in H358 and H441 cells, as evidenced by increased caspase 3 activity and cleavage of pro-caspase 9 and PARP, but not in H460 or A549 cells. The apoptotic effect of erlotinib in the sensitive H358 cells was associated with downregulation of CIP2A, increase in PP2A activity and decrease in AKT phosphorylation. Overexpression of CIP2A and AKT protected the sensitive H358 cells from erlotinib-induced apoptosis. Knockdown of CIP2A gene expression by siRNA enhanced the erlotinib-induced apoptotic in the resistant H460 cells that resembled the sensitive H358 cells. Erlotinib also inhibited the growth of H358 tumors in nude mice. CONCLUSIONS: The CIP2A-dependent pathway mediates the tumoricidal effects of erlotinib on NSCLC cells without EGFR mutations in vitro and in vivo. CIP2A may be a novel molecular target against NSCLC for future drug development.
BACKGROUND:Epidermal growth factor receptor (EGFR) inhibitors show favorable clinical response in some patients with non-small cell lung cancer (NSCLC) who have no EGFR mutation, indicating alternative mechanisms for their tumoricidal effects. We previously showed erlotinib, a selective EGFR antagonist, inhibited the growth of sensitive hepatocellular carcinoma cells by inhibiting the cancerous inhibitor of protein phosphatase 2A (CIP2A) pathway. The aim of this study was to determine if erlotinib can also inhibit the growth of NSCLC cells by inactivating the CIP2A-dependent signaling pathway. METHODS: Four NSCLC cell lines (H358 H441 H460 and A549) were treated with erlotinib to determine their sensitivity to erlotinib-induced cell death and apoptosis. Expression of CIP2A and the downstream AKT were analyzed. The effects of CIP2A on erlotinib-induced apoptosis were confirmed by overexpression of CIP2A and knockdown of CIP2A gene expression in the sensitive cells and resistant cells, respectively. In vivo efficacy of erlotinib against H358 xenograft tumor was also determined in nude mice. RESULTS:Erlotinib induced significant cell death and apoptosis in H358 and H441 cells, as evidenced by increased caspase 3 activity and cleavage of pro-caspase 9 and PARP, but not in H460 or A549 cells. The apoptotic effect of erlotinib in the sensitive H358 cells was associated with downregulation of CIP2A, increase in PP2A activity and decrease in AKT phosphorylation. Overexpression of CIP2A and AKT protected the sensitive H358 cells from erlotinib-induced apoptosis. Knockdown of CIP2A gene expression by siRNA enhanced the erlotinib-induced apoptotic in the resistant H460 cells that resembled the sensitive H358 cells. Erlotinib also inhibited the growth of H358 tumors in nude mice. CONCLUSIONS: The CIP2A-dependent pathway mediates the tumoricidal effects of erlotinib on NSCLC cells without EGFR mutations in vitro and in vivo. CIP2A may be a novel molecular target against NSCLC for future drug development.
Authors: Ming Zhao; Erin W Howard; Amanda B Parris; Zhiying Guo; Qingxia Zhao; Zhikun Ma; Ying Xing; Bolin Liu; Susan M Edgerton; Ann D Thor; Xiaohe Yang Journal: Oncotarget Date: 2017-07-19