Erlotinib promotes endoplasmic reticulum stress-mediated injury in the intestinal epithelium.
Erlotinib, a popular drug for treating non-small cell lung cancer (NSCLC), causes diarrhea in approximately 55% of patients receiving this drug. In the present study, we found that erlotinib induced barrier dysfunction in rat small intestine epithelial cells (IEC-6) by increasing epithelial permeability and down-regulating E-cadherin. The mRNA levels of various pro-inflammatory cytokines (Il-6, Il-25 and Il-17f) were increased after erlotinib treatment in IEC-6 cells. Erlotinib concentration- and time-dependently induced apoptosis and endoplasmic reticulum (ER) stress in both IEC-6 and human colon epithelial cells (CCD 841 CoN). Intestinal epithelial injury was also observed in male C57BL/6J mice administrated with erlotinib. Knockdown of C/EBP homologous protein (CHOP) with small interference RNA partially reversed erlotinib-induced apoptosis, production of IL-6 and down-regulation of E-cadherin in cultured intestinal epithelial cells. In conclusion, erlotinib caused ER stress-mediated injury in the intestinal epithelium, contributing to its side effects of diarrhea in patients.
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
Lu
L
Fan
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
Lingna
L
Hu
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
Baofang
B
Yang
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
Xianying
X
Fang
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
Zhe
Z
Gao
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
Wanshuai
W
Li
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
Yang
Y
Sun
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
Yan
Y
Shen
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
Xuefeng
X
Wu
Department of Clinical Oncology, The First Affiliated Hospital of Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China.
Yongqian
Y
Shu
Department of Clinical Oncology, The First Affiliated Hospital of Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China. Electronic address: guluer@163.com.
Yanhong
Y
Gu
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China. Electronic address: xudongwu@nju.edu.cn.
Xudong
X
Wu
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China. Electronic address: molpharm@163.com.
Qiang
Q
Xu
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D015820:Cadherins / Q000378:metabolism; D002460:Cell Line; D003967:Diarrhea / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D000069347:Erlotinib Hydrochloride; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010539:Permeability; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D011799:Quinazolines / Q000633:toxicity*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D000970:Antineoplastic Agents; D015820:Cadherins; C497251:Ddit3 protein, rat; D018836:Inflammation Mediators; D020381:Interleukin-17; D015850:Interleukin-6; D007378:Interleukins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; C504693:interleukin-25, rat; D051742:Transcription Factor CHOP; D000069347:Erlotinib Hydrochloride
Apoptosis; Diarrhea; E-cadherin; ER stress; Erlotinib