SAHA, an HDAC inhibitor, overcomes erlotinib resistance in human pancreatic cancer cells by modulating E-cadherin.
Pancreatic cancer is one of the most lethal cancers and remains a major unsolved health problem. Less than 20 % of patients are surgical candidates, and the median survival for non-resected patients is approximately 3 to 4 months. Despite the existence of many conventional cancer therapies, few targeted therapies have been developed for pancreatic cancer. Combination therapy using erlotinib and gemcitabine is an approved standard chemotherapy for advanced pancreatic cancer, but it has marginal therapeutic benefit. To try to improve the therapeutic outlook, we studied the efficacy of another combination treatment and the relevance to E-cadherin in human pancreatic cancer cells. We treated two human pancreatic cancer cell lines with the histone deacetylase inhibitor (HDACi) SAHA. Interestingly, in these Panc-1 and Capan1 cells, we observed that the expression levels of E-cadherin and phosphorylated EGFR were gradually upregulated after treatment with SAHA. Furthermore, these cells underwent induced cell death after exposure to the combination treatment of SAHA and erlotinib. In Panc-1 cells, overexpression of E-cadherin activated the phosphorylation of EGFR and increased the cell sensitivity to erlotinib. In Capan1 cells, knocking down E-cadherin decreased the expression of phosphorylated EGFR, and these cells did not respond to erlotinib. Therefore, we demonstrated the efficacy of the combined treatment with SAHA and erlotinib in human pancreatic cancer cells, and we determined that the increased efficacy was due, at least in part, to the effects of SAHA on the expression of E-cadherin. Our studies suggest that E-cadherin may be a potent biomarker for pancreatic cancer.
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Seong Joon
SJ
Park
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.|Department of Biosciences and Bioinformatics, Myongji University, 116 Myongji-ro, Cheoin-gu, Yongin-si, Gyeonggi-do, 449-728, Republic of Korea.
Seung-Mi
SM
Kim
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Jai-Hee
JH
Moon
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Jeong Hee
JH
Kim
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Jae-Sik
JS
Shin
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Seung-Woo
SW
Hong
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Yu Jin
YJ
Shin
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Dae-Hee
DH
Lee
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Eun Young
EY
Lee
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Ih-Yeon
IY
Hwang
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Jeong Eun
JE
Kim
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Kyu-Pyo
KP
Kim
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Yong Sang
YS
Hong
Department of Biosciences and Bioinformatics, Myongji University, 116 Myongji-ro, Cheoin-gu, Yongin-si, Gyeonggi-do, 449-728, Republic of Korea.
Won-Keun
WK
Lee
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.|Department of Radiation Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Eun Kyung
EK
Choi
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Jung Shin
JS
Lee
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. inno183@amc.seoul.kr.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. inno183@amc.seoul.kr.|Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. inno183@amc.seoul.kr.
Dong-Hoon
DH
Jin
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. twkimmd@amc.seoul.kr.|Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. twkimmd@amc.seoul.kr.
Tae Won
TW
Kim
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077337:Vorinostat; D000093542:Gemcitabine
D015820:Cadherins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D003841:Deoxycytidine; D000077337:Vorinostat; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000093542:Gemcitabine
Cell death; E-cadherin; Erlotinib; Human pancreatic cancer cells; SAHA