Distinct effects of SIRT1 in cancer and stromal cells on tumor promotion
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Dong Hoon Shin1,2, Yong-Joon Choi3, Peng Jin3, Haejin Yoon3, Yang-Sook Chun3,4, Hyun-Woo Shin1,3,4, Ja-Eun Kim5, Jong-Wan Park1,3,4
1Department of Pharmacology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea
2Lung Cancer Branch, Division of Translational & Clinical Research, Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Gyeonggi-do 410-769, Republic of Korea
3Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea
4Ischemic/Hypoxic Disease Institute and Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea
5Department of Pharmacology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
Jong-Wan Park, email: firstname.lastname@example.org
Keywords: SIRT1, tumor, stroma, MMP3
Received: November 14, 2015 Accepted: February 28, 2016 Published: March 14, 2016
The lysyl deacetylase SIRT1 acts as a metabolic sensor in adjusting metabolic imbalance. To explore the role of SIRT1 in tumor-stroma interplay, we designed an in vivo tumor model using SIRT1-transgenic mice. B16F10 mouse melanoma grew more quickly in SIRT1-transgenic mice than in wild-type mice, whereas SIRT1-overexpressing one grew slowly in both mice. Of human tumors, SIRT1 expression in stromal fibroblasts was found to correlate with poor prognosis in ovarian cancer. B16F10 and human ovarian cancer (SKOV3 and SNU840) cells were more proliferative in co-culture with SIRT1-overexpressiong fibroblasts. In contrast, SIRT1 within cancer cells has a negative effect on cell proliferation. In conditioned media from SIRT1-overexpressing fibroblasts, matrix metalloproteinase-3 (MMP3) was identified in cytokine arrays to be secreted from fibroblasts SIRT1-dependently. Fibroblast-derived MMP3 stimulated cancer cell proliferation, and such a role of MMP3 was also demonstrated in cancer/fibroblast co-grafts. In conclusion, SIRT1 plays differential roles in cancer and stromal cells. SIRT1 in stromal cells promotes cancer growth by producing MMP3, whereas SIRT1 in cancer cells inhibits growth via an intracellular event. The present study provides a basis for setting new anticancer strategies targeting SIRT1.
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