Enforced expression of a truncated form of Bax-alpha (tBax) driven by human telomerase reverse transcriptase (hTERT) promoter sensitizes tumor cells to chemotherapeutic agents or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).
BACKGROUND
We have recently demonstrated that a truncated form of the pro-apoptotic molecule Bax-alpha (tBax) at the NH2-terminus is more potent in inducing cell death than wild-type (wt) Bax. In the present study, whether efficient cell death is induced by tBax expression from human telomerase reverse transcriptase (hTERT) promoter, which is highly active in tumor but not normal cells, was examined.


METHODS
Cell death was assessed by luciferase reporter assay and the annexin staining method.


RESULTS
Enforced expression of tBax resulted in cell death to a greater extent than wt Bax in two types of tumor cells: osteogenic sarcoma MG-63 and squamous cell carcinoma MIT7. The tBax sensitized these tumor cells to death induced by chemotherapeutic agents. Moreover, tBax enhanced cell death induced by the tumor necrosis factor-related apoptosis-inducing ligand to a high level, compared with wt Bax. Furthermore, tBax efficiently induced death of the MG-63 cells overexpressing Bcl-x(L), compared with wt Bax.


CONCLUSIONS
tBax alone, or in combination with chemotherapeutic agents, would be a promising candidate for human gene therapy in the setting of carcinoma, especially for tumors containing high levels of Bcl-x(L).
Department of Immunology and Intractable Immune Disease Research Center, Tokyo Medical University, Shinjuku-ku 160-8402, Tokyo, Japan.
Hiroko
H
Toyota
Seiji
S
Kondo
Satoru
S
Kyo
Junichiro
J
Mizuguchi
D000970:Antineoplastic Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D016190:Carboplatin / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics; D005047:Etoposide / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D012516:Osteosarcoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D053221:TNF-Related Apoptosis-Inducing Ligand; D019098:Telomerase / Q000235:genetics; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051020:bcl-X Protein / Q000096:biosynthesis
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D005047:Etoposide; D016190:Carboplatin; D019098:Telomerase; D002945:Cisplatin