Down-regulation of BRCA2 expression by collagen type I promotes prostate cancer cell proliferation.
BRCA2 is a tumor suppressor gene that when mutated confers an increased susceptibility to developing breast and prostate carcinoma. Besides its role in mediating DNA repair, new evidence suggests that BRCA2 may also play a role in suppressing cancer cell growth. Because altered interactions between neoplastic cells and the surrounding extracellular matrix (ECM) play a pivotal role in unchecked cancer cell proliferation and metastatic progression, we hypothesized that the ECM may have an effect in BRCA2 expression. By using normal and prostate carcinoma cell lines, we demonstrated that although normal cells transiently increase BRCA2 protein levels when adhering to the ECM protein collagen type I (COL1), carcinoma cells exhibit a significant reduction in BRCA2 protein. This aberrant effect is independent from de novo protein synthesis and results from COL1-beta(1) integrin signaling through phosphatidylinositol (PI) 3-kinase leading to BRCA2 ubiquitination and degradation in the proteasome. BRCA2 protein depletion after cancer cell adhesion to COL1 or in small RNA interference assays triggers new DNA synthesis, a trophic effect that is abrogated by recombinant BRCA2 expression. Blocking or inhibiting beta(1) integrin, PI 3-kinase, or proteasome activity all have a negative effect on COL1-mediated DNA synthesis in cancer cells. In normal cells, the transient increase in BRCA2 expression is independent from beta(1) integrin or PI 3-kinase and has no effect in cell proliferation. In summary, these results unravel a novel mechanism whereby prostate carcinoma cell proliferation is enhanced by the down-regulation of BRCA2 expression when interacting with COL1, a major component of the ECM at osseous metastatic sites.
Moro
Loredana
L
Institute of Biomembranes and Bioenergetics, National Research Council (Consiglio Nazionale delle Ricerche), Via Amendola 165/A, Bari 70126, Italy. l.moro@ibbe.cnr.it
Arbini
Arnaldo A
AA
Marra
Ersilia
E
Greco
Margherita
M
D024682:BRCA2 Protein / Q000096:biosynthesis* / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D024042:Collagen Type I / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004260:DNA Repair; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D024522:Genes, BRCA2; D005822:Genetic Vectors; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D019012:Integrin beta1 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D008297:Male; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013696:Temperature; D013936:Thymidine / Q000737:chemistry; D013997:Time Factors; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism
D024682:BRCA2 Protein; D024042:Collagen Type I; D019012:Integrin beta1; D016023:Integrins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D025801:Ubiquitin; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D046988:Proteasome Endopeptidase Complex; D013936:Thymidine