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Targeting Notch signaling by γ-secretase inhibitor I enhances the cytotoxic effect of 5-FU in gastric cancer

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Abstract

Current medication for gastric cancer patients has a low success rate and the patients develop rapid tolerance to these drugs. Therefore, the development of new regimens is desired. In this study, we determined that Notch-signaling-related genes were overexpressed and activated in gastric cancer patients and gastric cancer cell lines. According to recent studies, γ-secretase inhibitors (GSIs), which function as Notch signaling inhibitors, could be used as therapeutic drugs in cancer. We demonstrated that GSI I (cbz-IL-CHO) is the most effective GSI in gastric cancer cells. We also determined the cell survival signaling-related proteins that were affected by GSI I. The levels of phosphorylated AKT were significantly decreased upon GSI I treatment, and constitutively activated myristoylated AKT completely blocked GSI I-induced apoptosis and cell survival, suggesting that inhibition of AKT signaling is critical for GSI I-mediated effects in gastric cancer cells. In order to maximize the effects and safety of GSI I, a combination treatment with GSI I and 5-FU was performed. Inhibition of gastric cancer cell proliferation with the combination treatment was significantly better than that with the single treatment. All phosphorylated forms of AKT, p44/42, JNK, and p38 were drastically changed by the combination treatment. Orthotopically transplanted gastric tumor burdens in mice were reduced using the combined treatment. The outcomes of this study clearly demonstrated the therapeutic potential of GSI I in gastric cancer, as well as the greater efficacy of the combined treatment of GSI I with 5-FU. Therefore, we suggest that further clinical trials examining the potential of combined GSI I and 5-FU treatment in gastric cancer patients be undertaken.

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Abbreviations

GSI:

γ-Secretase inhibitor

AGC:

Advanced gastric cancer

T-ALL:

T cell acute lymphoblastic leukemia

NICD1:

Notch-1 intracellular domain

NICD2:

Notch-2 intracellular domain

Myr-AKT:

Myristoylated AKT (constitutively active form of AKT)

LRP:

Low-density lipoprotein receptor-related protein

EMT:

Epithelial-mesenchymal transition

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Acknowledgments

We thank Dr. Ryoichiro Kegeyama for kindly providing the pHES1-luc reporter gene construct. This project was supported by a Grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI11C0926 and A121982), the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (No. NRF-2014R1A2A1A11050600), and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (No. NRF-2010-0022436).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea

    Hyun-Woo Lee, Seok-Jun Kim & Kyung-Hee Chun

  2. Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea

    Hyun-Woo Lee & Jaewhan Song

  3. Center for Gastric Cancer, National Cancer Center, Goyang, Republic of Korea

    Il Ju Choi

  4. Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea

    Seok-Jun Kim & Kyung-Hee Chun

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  1. Hyun-Woo Lee
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Correspondence to Kyung-Hee Chun.

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Lee, HW., Kim, SJ., Choi, I.J. et al. Targeting Notch signaling by γ-secretase inhibitor I enhances the cytotoxic effect of 5-FU in gastric cancer. Clin Exp Metastasis 32, 593–603 (2015). https://doi.org/10.1007/s10585-015-9730-5

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