Genetic ablation of Bcl-x attenuates invasiveness without affecting apoptosis or tumor growth in a mouse model of pancreatic neuroendocrine cancer.
Tumor cell death is modulated by an intrinsic cell death pathway controlled by the pro- and anti-apoptotic members of the Bcl-2 family. Up-regulation of anti-apoptotic Bcl-2 family members has been shown to suppress cell death in pre-clinical models of human cancer and is implicated in human tumor progression. Previous gain-of-function studies in the RIP1-Tag2 model of pancreatic islet carcinogenesis, involving uniform or focal/temporal over-expression of Bcl-x(L), demonstrated accelerated tumor formation and growth. To specifically assess the role of endogenous Bcl-x in regulating apoptosis and tumor progression in this model, we engineered a pancreatic beta-cell-specific knockout of both alleles of Bcl-x using the Cre-LoxP system of homologous recombination. Surprisingly, there was no appreciable effect on tumor cell apoptosis rates or on tumor growth in the Bcl-x knockout mice. Other anti-apoptotic Bcl-2 family members were expressed but not substantively altered at the mRNA level in the Bcl-x-null tumors, suggestive of redundancy without compensatory transcriptional up-regulation. Interestingly, the incidence of invasive carcinomas was reduced, and tumor cells lacking Bcl-x were impaired in invasion in a two-chamber trans-well assay under conditions mimicking hypoxia. Thus, while the function of Bcl-x in suppressing apoptosis and thereby promoting tumor growth is evidently redundant, genetic ablation implicates Bcl-x in selectively facilitating invasion, consistent with a recent report documenting a pro-invasive capability of Bcl-x(L) upon exogenous over-expression.
Hager
Jeffrey H
JH
Diabetes and Hellen Diller Family Comprehensive Cancer Centers, Department of Biochemistry & Biophysics, University of California San Francisco, San Francisco, California, United States of America.
Ulanet
Danielle B
DB
Hennighausen
Lothar
L
Hanahan
Douglas
D
D000818:Animals; D017209:Apoptosis; D002465:Cell Movement; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D020690:GTPase-Activating Proteins / Q000378:metabolism; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000473:pathology*; D009928:Organ Specificity; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics; D051020:bcl-X Protein / Q000172:deficiency* / Q000378:metabolism
D020690:GTPase-Activating Proteins; C490620:Ralbp1 protein, mouse; D051020:bcl-X Protein