Apoptosis caused by chemotherapeutic inhibition of nuclear factor-kappaB activation.
Both the protein kinase C (alpha/beta) inhibitor Go6976 and expression of dominant-negative nuclear factor (NF)-kappaB inhibitor kinase mutants: (a) blocked the growth and caused regression of a mammary tumor insyngeneic mice; (b) inhibited epidermal growth factor (EGF)-induced activation, nuclear translocation, and DNA-binding activity of NF-kappaB; and (c) caused apoptosis of EGF-stimulated cultured mammary tumor cells. cDNA microarray analysis revealed that these treatments reversed the expression changes of a subset of genes altered by EGF treatment. These included: up-regulation of proapoptotic genes of the tumor necrosis factor (TNF) pathway, death-associated protein (DAP) kinase, p53, and p21/Waf1; and down-regulation of inhibitors of apoptosis: inhibitor of apoptosis(IAP)-1 and X-IAP, TNF receptor-associated factor (TRAF)-2, and factors OX40 and 4-1BB. These results and our previous studies suggest the practicality of a target-directed chemotherapy for EGF-responsive breast cancers, by blocking NF-kappaB activation and thereby reinstating apoptosis.
Biswas
Debajit K
DK
Dana-Farber Cancer Institute, Department of Cancer Biology, Boston, Massachusetts 02115, USA. Debajit_Biswas@dfci.harvard.edu
Martin
Katherine J
KJ
McAlister
Cliona
C
Cruz
Antonio P
AP
Graner
Edgard
E
Dai
Sun-chun
SC
Pardee
Arthur B
AB
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D002227:Carbazoles / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D051550:I-kappa B Kinase; D007211:Indoles / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008805:Mice, Inbred A; D009154:Mutation; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured
D002227:Carbazoles; D007211:Indoles; D016328:NF-kappa B; C081021:Go 6976; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse