IFNgamma sensitization to TRAIL-induced apoptosis in human thyroid carcinoma cells by upregulating Bak expression.
TRAIL preferentially induces apoptosis in tumor cells and virus-infected cells. Unlike other tumor necrosis factor family members, TRAIL does not kill cells from most normal tissues and has thus been proposed as a promising new cancer treatment. Our study demonstrated that IFNgamma combined with TRAIL can trigger apoptosis in vitro in several resistant thyroid tumor cell lines, such as thyroid anaplastic carcinoma cells (ARO cells), while either agent alone exerts only a minimal effect. We further tested this effect on a mouse thyroid tumor model, when in vivo tumor growth was also significantly inhibited by this combination. The mechanism of how IFNgamma sensitized thyroid carcinoma cells to TRAIL-induced apoptosis was investigated by screening global gene alterations in ARO cells treated with IFNgamma. Microarray data revealed that a proapoptotic gene, Bak, is markedly upregulated by IFNgamma, and this was confirmed by RNase protection assay. Western blot analysis also showed a significant increase in Bak at the protein level. Upregulation of Bak and sensitization for apoptosis by IFNgamma was blocked by overexpression of antisense Bak in ARO cells. Furthermore, overexpression of Bak sensitized ARO cell to TRAIL-induced apoptosis without the need for IFNgamma pretreatment. This suggests that Bak is a regulatory molecule involved in IFNgamma-facilitated TRAIL-mediated apoptosis in thyroid cancer cells.
Wang
Su He
SH
Department of Medicine, University of Michigan Medical Center, Ann Arbor, MI, USA.
Mezosi
Emese
E
Wolf
Julie M
JM
Cao
Zhengyi
Z
Utsugi
Saho
S
Gauger
Paul G
PG
Doherty
Gerard M
GM
Baker
James R
JR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D053221:TNF-Related Apoptosis-Inducing Ligand; D013964:Thyroid Neoplasms / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*; D050998:bcl-2 Homologous Antagonist-Killer Protein
D051017:Apoptosis Regulatory Proteins; C494772:BAK1 protein, human; C494773:Bak1 protein, mouse; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D050998:bcl-2 Homologous Antagonist-Killer Protein; D007371:Interferon-gamma