title: The combination of tetraiodothyroacetic acid and cetuximab inhibits cell proliferation in colorectal cancers with different K-ras status.
abstract: Thyroid hormone induces cancer cell proliferation through its cell surface receptor integrin αvβ3. Acting via integrin αvβ3, the deaminated T4 analog tetraiodothyroacetic acid (tetrac), and its nanoparticle formulation nano-diamino-tetrac (NDAT) could inhibit cell proliferation and xenograft growth. In this study, we investigated the T4 effects on proliferation in colorectal cancer cell lines based on the proliferation marker expressions at both mRNA and protein levels. The effects of tetrac/NDAT, the monoclonal anti-EGFR antibody cetuximab, and their combinations on colorectal cancer cell proliferation were examined according to the relevant gene expression profiles and cell count analysis. The results showed that T4 significantly enhanced PCNA, Cyclin D1 and c-Myc levels in both K-ras wild type HT-29 and mutant HCT 116 cells. In HCT 116 cells, the combination of NDAT and cetuximab significantly suppressed the mRNA expressions of proliferative genes PCNA, Cyclin D1, c-Myc and RRM2 raised by T4 compared to cetuximab alone. In addition, T4-suppressed mRNA expressions of pro-apoptotic genes p53 and RRM2B could be significantly elevated by the combination of NDAT and cetuximab compared to cetuximab alone. In the K-ras mutant HCT 116 cells, but not in the K-ras wild type COLO 205 cells, the combinations of tetrac/NDAT and cetuximab significantly reduced cell proliferation compared to cetuximab alone. In conclusion, T4 promoted colorectal cancer cell proliferation which could be repressed by tetrac and NDAT. The combinations of tetrac/NDAT and cetuximab potentiated cetuximab actions in K-ras mutant colorectal cancer cells.
authors.affiliation: Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan.
authors.forename: Yee-Shin
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Tang
authors.initials: YT
authors.lastname: Chin
authors.affiliation: Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Chen S H
authors.initials: YSH
authors.lastname: Yang
authors.affiliation: Division of General Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Po-Li
authors.initials: PL
authors.lastname: Wei
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Han-Chung
authors.initials: HC
authors.lastname: Wu
authors.affiliation: National Laboratory Animal Center, National Applied Research Laboratories, Taiwan.
authors.forename: Ai
authors.initials: A
authors.lastname: Shih
authors.affiliation: Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yueh-Tong
authors.initials: YT
authors.lastname: Lu
authors.affiliation: Department of Biology, University Tor Vergata, Rome, Italy.
authors.forename: Jens Z
authors.initials: JZ
authors.lastname: Pedersen
authors.affiliation: Department of Sciences, University Roma Tre, Rome, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Incerpi
authors.affiliation: Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan.
authors.forename: Leroy F
authors.initials: LF
authors.lastname: Liu
authors.affiliation: Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan; Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan. Electronic address: linhy@tmu.edu.tw.
authors.forename: Hung-Yun
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA; Albany Medical College, Albany, NY, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Davis
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D016259:Genes, myc / Q000235:genetics; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D012337:RNA, Ribosomal, 18S / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013963:Thyroid Hormones / Q000494:pharmacology; D013974:Thyroxine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D018809:Proliferating Cell Nuclear Antigen; D012337:RNA, Ribosomal, 18S; D013963:Thyroid Hormones; D019938:Cyclin D1; C011126:tetraiodothyroacetic acid; D000068818:Cetuximab; D013974:Thyroxine
keywords: Cetuximab; Colorectal cancer; NDAT; Tetrac; Thyroid hormone