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Tumour Biol. 2016 Apr;37(4):4323-30. doi: 10.1007/s13277-015-4216-2. Epub 2015 Oct 22.

SAHA, an HDAC inhibitor, overcomes erlotinib resistance in human pancreatic cancer cells by modulating E-cadherin.

Park SJ1,2, Kim SM1,2,3, Moon JH1,2, Kim JH1,2, Shin JS1,2, Hong SW1,2, Shin YJ1,2, Lee DH1,2, Lee EY1,2, Hwang IY1,2, Kim JE1,2, Kim KP1,2, Hong YS1,2, Lee WK3, Choi EK1,4, Lee JS1,2, Jin DH5,6,7, Kim TW8,9.

Author information

1
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.
2
Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
3
Department of Biosciences and Bioinformatics, Myongji University, 116 Myongji-ro, Cheoin-gu, Yongin-si, Gyeonggi-do, 449-728, Republic of Korea.
4
Department of Radiation Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
5
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. inno183@amc.seoul.kr.
6
Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. inno183@amc.seoul.kr.
7
Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. inno183@amc.seoul.kr.
8
Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. twkimmd@amc.seoul.kr.
9
Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. twkimmd@amc.seoul.kr.

Abstract

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.

KEYWORDS:

Cell death; E-cadherin; Erlotinib; Human pancreatic cancer cells; SAHA

PMID:
26493999
DOI:
10.1007/s13277-015-4216-2
[Indexed for MEDLINE]

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