title: Study of Arsenic Sulfide in Solid Tumor Cells Reveals Regulation of Nuclear Factors of Activated T-cells by PML and p53.
abstract: Arsenic sulfide (AS) has excellent cytotoxic activity in acute promyelocytic leukemia (APL) but its activity in solid tumors remains to be explored. Here we show that AS and cyclosporine A (CsA) exerted synergistic inhibitory effect on cell growth and c-Myc expression in HCT116 cells. AS inhibited the expression of PML, c-Myc, NFATc1, NFATc3, and NFATc4, while stimulating the expression of p53 and NFATc2. Knockdown of PML reduced NFATc1, NFATc2, NFATc3 and NFATc4 expression while overexpression of p53 stimulated NFATc2-luciferase activity that was further augmented by AS by binding to a set of p53 responsive elements (PREs) on the NFATc2 promoter. Additionally, overexpression of p53 suppressed NFATc3 and NFATc4. Reciprocally, NFATc3 knockdown enhanced p53 while reducing MDM2 expression indicating that NFATc3 is a negative regulator of p53 while a positive regulator of MDM2, consistent with its tumor-promoting property as knockdown of NFATc3 retarded cell growth in vitro and tumor growth in xenograft. In patients with colon cancer, tumor expression of NFATc2 correlated with superior survival, while nuclear NFATc1 with inferior survival. These results indicate that AS differentially regulates NFAT pathway through PML and p53 and reveal an intricate reciprocal regulatory relationship between NFAT proteins and p53 pathway.
authors.affiliation: Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Wenping
authors.initials: W
authors.lastname: Ding
authors.affiliation: Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Tong
authors.affiliation: Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Oncology and Hematology, Kaiser Permanente Medical Center, Santa Clara, CA.|Kaiser Permanente Division of Research, Oakland, CA, USA.
authors.forename: Minggui
authors.initials: M
authors.lastname: Pan
authors.affiliation: Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Siyu
authors.initials: S
authors.lastname: Chen
mesh_terms: D001152:Arsenicals / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D016572:Cyclosporine / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D000071156:Promyelocytic Leukemia Protein / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D001152:Arsenicals; D050778:NFATC Transcription Factors; D000071156:Promyelocytic Leukemia Protein; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D013440:Sulfides; D016159:Tumor Suppressor Protein p53; C070576:PML protein, human; C045816:arsenic trisulfide; D016572:Cyclosporine