title: The influence of the BRAF V600E mutation in thyroid cancer cell lines on the anticancer effects of 5-aminoimidazole-4-carboxamide-ribonucleoside.
abstract: 5-Aminoimidazole-4-carboxamide-ribonucleoside (AICAR) is an activator of 5'-AMP-activated protein kinase (AMPK), which plays a role in the maintenance of cellular energy homeostasis. Activated AMPK inhibits the protein kinase mechanistic target of rapamycin, thereby reducing the extent of protein translation and suppressing both cell growth and cell cycle entry. Recent reports indicate that AMPK-mediated growth inhibition is achieved via an action of the RAF-MEK-ERK mitogen-activated protein kinase pathway in melanoma cells harboring the V600E mutant form of the BRAF oncogene. In this study, we investigated the anti-cancer efficacy of AICAR by measuring its effects on proliferation, apoptosis, and cell cycle progression of BRAF wild-type and V600E-mutant thyroid cancer cell lines. We also explored the mechanism underlying these effects. AICAR inhibited the proliferation of BRAF V600E-mutant thyroid cancer cell lines more strongly than was the case with wild-type cell lines. The suppressive effect of AICAR on cell proliferation was associated with increased S-phase cell cycle arrest and apoptosis. Interestingly, AICAR suppressed phosphorylation of ERK and p70S6K in BRAF V600E-mutant thyroid cancer cells, but rather increased phosphorylation in wild-type cells. Together, the results indicate that AICAR-induced AMPK activation in BRAF V600E-mutant thyroid cancer cell lines resulted in increases in apoptosis and S-phase arrest via downregulation of ERK and p70S6K activity. Thus, regulation of AMPK activity may be potentially useful as a therapy for thyroid cancer if the cancer harbors a BRAF V600E mutation.
authors.affiliation: Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, 86 Asanbyeongwon-gil, Songpa-gu, Seoul 138-736, Republic of Korea.
authors.forename: Hyun-Jeung
authors.initials: HJ
authors.lastname: Choi
authors.forename: Tae Yong
authors.initials: TY
authors.lastname: Kim
authors.forename: Namhyun
authors.initials: N
authors.lastname: Chung
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Yim
authors.forename: Won Gu
authors.initials: WG
authors.lastname: Kim
authors.forename: Jin A
authors.initials: JA
authors.lastname: Kim
authors.forename: Won Bae
authors.initials: WB
authors.lastname: Kim
authors.forename: Young Kee
authors.initials: YK
authors.lastname: Shong
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004734:Energy Metabolism / Q000502:physiology; D006801:Humans; D009154:Mutation / Q000235:genetics*; D011494:Protein Kinases / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012265:Ribonucleotides / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D011494:Protein Kinases; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000091162:AMP-Activated Protein Kinase Kinases; C031143:AICA ribonucleotide