Dipeptidyl Peptidase 9 Increases Chemoresistance and is an Indicator of Poor Prognosis in Colorectal Cancer
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ORIGINAL ARTICLE – TRANSLATIONAL RESEARCH AND BIOMARKERS
Dipeptidyl Peptidase 9 Increases Chemoresistance and is an Indicator of Poor Prognosis in Colorectal Cancer Kazuhiro Saso, MD1, Norikatsu Miyoshi, MD, PhD, FICS, FACS1 , Shiki Fujino, MD, PhD1, Masaru Sasaki, MD1, Masayoshi Yasui, MD, PhD2, Masayuki Ohue, MD, PhD2, Takayuki Ogino, MD, PhD1, Hidekazu Takahashi, MD, PhD1, Mamoru Uemura, MD, PhD1, Chu Matsuda, MD, PhD1, Tsunekazu Mizushima, MD, PhD1, Yuichiro Doki, MD, PhD1, and Hidetoshi Eguchi, MD, PhD1 1
Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan; 2Department of Surgery, Osaka International Cancer Institute, Osaka, Japan
ABSTRACT Background. In recent years, systemic chemotherapy has significantly improved the prognosis of metastatic colorectal cancer (CRC); however, different patients have different responses to chemotherapeutics. Methods. Dipeptidyl peptidase 9 (DPP9) is an enzyme in the dipeptidyl peptidase IV family that has been reported to increase drug sensitivity in acute myeloid leukemia. In this study, we examined the relationship between DPP9 expression and the prognosis of patients with CRC, as well as the role of DPP9 in anticancer drug resistance. Moreover, the effects of the DPP9 inhibitors talabostat and vildagliptin in CRC cell lines and primary cultured cells were assessed. Results. High expression of DPP9 was associated with worse prognosis in 196 patients with CRC. Cell viability was markedly inhibited in CRC cell lines transfected with DPP9 small interfering RNA or small hairpin RNA. Talabostat suppressed proliferation in CRC cell lines and primary cultured cells, and increased their sensitivity to chemotherapy. Vildagliptin, a DPP family inhibitor currently administered for diabetes, also increased the sensitivity of CRC cells to anticancer drugs.
Electronic supplementary material The online version of this article (https://doi.org/10.1245/s10434-020-08729-7) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2020 First Received: 20 February 2020 N. Miyoshi, MD, PhD, FICS, FACS e-mail: [email protected]
Conclusion. DPP9 was a poor prognostic factor for CRC and could be a new therapeutic target, while vildagliptin could be used as a repositioned drug for CRC treatment.
Colorectal cancer (CRC) remains one of the leading causes of cancer-related death worldwide and is estimated to be the third most commonly diagnosed cancer and the third leading cause of cancer death in the US.1 In recent years, systemic chemotherapy has remarkably improved the prognosis of metastatic CRC.2 Many new drugs, such as cetuximab and bevacizumab, are currently in use and have extended the median survival of patients with metastatic CRC;3–5 however, resistance to chemotherapy remains a problem. There are individual differences among patients regarding the effects of drugs. Elucidation of the mechanisms of drug resistance and the development of more effective and less toxic therapeut
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