BACKGROUND: The active metabolite of vitamin D, 1α,25-dihydroxyvitamin D(3) (1,25D) reduces the growth of several prostate cancer cell lines, most commonly by inducing a cell-cycle arrest in G(1). This is mediated, in part, through down-regulation of c-Myc, a positive regulator of the transcription factor, E2F. There is evidence that prostate cancer cells lacking functional retinoblastoma protein (Rb), a negative regulator of E2F activity, are poorly responsive to 1,25D treatment. Since up to 60% of prostate cancers demonstrate a loss of heterozygosity for Rb, we sought to determine whether Rb is required for the growth inhibitory effects of 1,25D. METHODS: Using siRNA, Rb was reduced in C4-2 prostate cancer cells, and the response of cells to 1,25D treatment or depletion of c-myc measured by [(3)H]-thymidine incorporation and flow cytometry. The effects of 1,25D treatment on E2F levels and activity, and E2F target gene expression were also measured. RESULTS: 1,25D treatment and c-Myc depletion both cause a G(1) arrest inhibiting C4-2 cell proliferation independently of Rb. 1,25D reduces c-Myc expression and causes a decrease in E2F and E2F target genes. Bcl-2, an E2F target and positive regulator of C4-2 cell growth, also is down-regulated by 1,25D independently of Rb. CONCLUSIONS: Redundant growth inhibitory pathways compensate for the loss of Rb, and tumors lacking functional Rb may be responsive to 1,25D.
BACKGROUND: The active metabolite of vitamin D, 1α,25-dihydroxyvitamin D(3) (1,25D) reduces the growth of several prostate cancer cell lines, most commonly by inducing a cell-cycle arrest in G(1). This is mediated, in part, through down-regulation of c-Myc, a positive regulator of the transcription factor, E2F. There is evidence that prostate cancer cells lacking functional retinoblastoma protein (Rb), a negative regulator of E2F activity, are poorly responsive to 1,25D treatment. Since up to 60% of prostate cancers demonstrate a loss of heterozygosity for Rb, we sought to determine whether Rb is required for the growth inhibitory effects of 1,25D. METHODS: Using siRNA, Rb was reduced in C4-2 prostate cancer cells, and the response of cells to 1,25D treatment or depletion of c-myc measured by [(3)H]-thymidine incorporation and flow cytometry. The effects of 1,25D treatment on E2F levels and activity, and E2F target gene expression were also measured. RESULTS: 1,25D treatment and c-Myc depletion both cause a G(1) arrest inhibiting C4-2 cell proliferation independently of Rb. 1,25D reduces c-Myc expression and causes a decrease in E2F and E2F target genes. Bcl-2, an E2F target and positive regulator of C4-2 cell growth, also is down-regulated by 1,25D independently of Rb. CONCLUSIONS: Redundant growth inhibitory pathways compensate for the loss of Rb, and tumors lacking functional Rb may be responsive to 1,25D.
Authors: Jung-Sun Kim; Justin M Roberts; William E Bingman; Longjiang Shao; Jianghua Wang; Michael M Ittmann; Nancy L Weigel Journal: Endocrinology Date: 2014-06-13 Impact factor: 4.736
Authors: Vasiliki I Dimitrakopoulou; Ruth C Travis; Irene M Shui; Alison Mondul; Demetrius Albanes; Jarmo Virtamo; Antonio Agudo; Heiner Boeing; H Bas Bueno-de-Mesquita; Marc J Gunter; Mattias Johansson; Kay-Tee Khaw; Kim Overvad; Domenico Palli; Antonia Trichopoulou; Edward Giovannucci; David J Hunter; Sara Lindström; Walter Willett; J Michael Gaziano; Meir Stampfer; Christine Berg; Sonja I Berndt; Amanda Black; Robert N Hoover; Peter Kraft; Timothy J Key; Konstantinos K Tsilidis Journal: Am J Epidemiol Date: 2017-03-15 Impact factor: 4.897
Authors: Wei-Lin W Wang; Namita Chatterjee; Sridar V Chittur; JoEllen Welsh; Martin P Tenniswood Journal: Mol Cancer Date: 2011-05-18 Impact factor: 27.401
Authors: Justin M Roberts; Rebeca San Martin; D Badrajee Piyarathna; James G MacKrell; Guilherme V Rocha; Jeffery A Dodge; Cristian Coarfa; Venkatesh Krishnan; David R Rowley; Nancy L Weigel Journal: Oncotarget Date: 2017-07-04