title: The retinoblastoma protein regulates hypoxia-inducible genetic programs, tumor cell invasiveness and neuroendocrine differentiation in prostate cancer cells.
abstract: Loss of tumor suppressor proteins, such as the retinoblastoma protein (Rb), results in tumor progression and metastasis. Metastasis is facilitated by low oxygen availability within the tumor that is detected by hypoxia inducible factors (HIFs). The HIF1 complex, HIF1α and dimerization partner the aryl hydrocarbon receptor nuclear translocator (ARNT), is the master regulator of the hypoxic response. Previously, we demonstrated that Rb represses the transcriptional response to hypoxia by virtue of its association with HIF1. In this report, we further characterized the role Rb plays in mediating hypoxia-regulated genetic programs by stably ablating Rb expression with retrovirally-introduced short hairpin RNA in LNCaP and 22Rv1 human prostate cancer cells. DNA microarray analysis revealed that loss of Rb in conjunction with hypoxia leads to aberrant expression of hypoxia-regulated genetic programs that increase cell invasion and promote neuroendocrine differentiation. For the first time, we have established a direct link between hypoxic tumor environments, Rb inactivation and progression to late stage metastatic neuroendocrine prostate cancer. Understanding the molecular pathways responsible for progression of benign prostate tumors to metastasized and lethal forms will aid in the development of more effective prostate cancer therapies.
authors.affiliation: The Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Labrecque
authors.affiliation: The Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Mandeep K
authors.initials: MK
authors.lastname: Takhar
authors.affiliation: The Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nason
authors.affiliation: The Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Santacruz
authors.affiliation: The Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.|Department of Urologic Sciences, The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tam
authors.affiliation: The Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Shabnam
authors.initials: S
authors.lastname: Massah
authors.affiliation: Department of Urologic Sciences, The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Haegert
authors.affiliation: Department of Urologic Sciences, The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bell
authors.affiliation: Department of Urologic Sciences, The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Manuel
authors.initials: M
authors.lastname: Altamirano-Dimas
authors.affiliation: Department of Urologic Sciences, The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Colin C
authors.initials: CC
authors.lastname: Collins
authors.affiliation: The Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Frank J S
authors.initials: FJ
authors.lastname: Lee
authors.affiliation: The Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Gratien G
authors.initials: GG
authors.lastname: Prefontaine
authors.affiliation: Department of Urologic Sciences, The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cox
authors.affiliation: The Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Timothy V
authors.initials: TV
authors.lastname: Beischlag
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics*; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D000860:Hypoxia / Q000235:genetics*; D008297:Male; D009361:Neoplasm Invasiveness; D055099:Neuroendocrine Cells / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D016160:Retinoblastoma Protein
keywords: hypoxia; invasion; neuroendocrine differentiation; prostate cancer; retinoblastoma protein