title: Distinct effects of SIRT1 in cancer and stromal cells on tumor promotion.
abstract: 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.
authors.affiliation: Department of Pharmacology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.|Lung 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.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Shin
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Yong-Joon
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Peng
authors.initials: P
authors.lastname: Jin
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Haejin
authors.initials: H
authors.lastname: Yoon
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.|Ischemic/Hypoxic Disease Institute and Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Yang-Sook
authors.initials: YS
authors.lastname: Chun
authors.affiliation: Department of Pharmacology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.|Ischemic/Hypoxic Disease Institute and Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Hyun-Woo
authors.initials: HW
authors.lastname: Shin
authors.affiliation: Department of Pharmacology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
authors.forename: Ja-Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.|Ischemic/Hypoxic Disease Institute and Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Jong-Wan
authors.initials: JW
authors.lastname: Park
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002450:Cell Communication; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D056564:Sirtuin 1 / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D017077:Culture Media, Conditioned; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: MMP3; SIRT1; stroma; tumor