GADD45gamma: a New Vitamin D-regulated Gene That is Antiproliferative in Prostate Cancer Cells

Overview

Journal Endocrinology

Publisher Oxford University Press

Specialty Endocrinology

Date 2010 Aug 27

PMID 20739400

Citations 7

Authors

Omar Flores

Kerry L Burnstein

Affiliations

Soon will be listed here.

Abstract

1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] inhibits proliferation of normal and malignant prostate epithelial cells at least in part through inhibition of G1 to S phase cell cycle progression. The mechanisms of the antiproliferative effects of 1,25-(OH)2D3 have yet to be fully elucidated but are known to require the vitamin D receptor. We previously developed a 1,25-(OH)2D3-resistant derivative of the human prostate cancer cell line, LNCaP, which retains active vitamin D receptors but is not growth inhibited by 1,25-(OH)2D3. Gene expression profiling revealed two novel 1,25-(OH)2D3-inducible genes, growth arrest and DNA damage-inducible gene gamma (GADD45γ) and mitogen induced gene 6 (MIG6), in LNCaP but not in 1,25-(OH)2D3-resistant cells. GADD45γ up-regulation was associated with growth inhibition by 1,25-(OH)2D3 in human prostate cancer cells. Ectopic expression of GADD45γ in either LNCaP or ALVA31 cells resulted in G1 accumulation and inhibition of proliferation equal to or greater than that caused by 1,25-(OH)2D3 treatment. In contrast, ectopic expression of MIG6 had only minimal effects on cell cycle distribution and proliferation. Whereas GADD45γ has been shown to be induced by androgens in prostate cancer cells, up-regulation of GADD45γ by 1,25-(OH)2D3 was not dependent on androgen receptor signaling, further refuting a requirement for androgens/androgen receptor in vitamin D-mediated growth inhibition. These data introduce two novel 1,25-(OH)2D3-regulated genes and establish GADD45γ as a growth-inhibitory protein in prostate cancer. Furthermore, the induction of GADD45γ gene expression by 1,25-(OH)2D3 may mark therapeutic response in prostate cancer.

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References

Moeenrezakhanlou A, Nandan D, Reiner N . Identification of a calcitriol-regulated Sp-1 site in the promoter of human CD14 using a combined western blotting electrophoresis mobility shift assay (WEMSA). Biol Proced Online. 2008; 10:29-35. PMC: 2275043. DOI: 10.1251/bpo140. View

Palmer H, Gonzalez-Sancho J, Espada J, Berciano M, Puig I, Baulida J . Vitamin D(3) promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. J Cell Biol. 2001; 154(2):369-87. PMC: 2150773. DOI: 10.1083/jcb.200102028. View

Wali R, Kong J, Sitrin M, Bissonnette M, Li Y . Vitamin D receptor is not required for the rapid actions of 1,25-dihydroxyvitamin D3 to increase intracellular calcium and activate protein kinase C in mouse osteoblasts. J Cell Biochem. 2003; 88(4):794-801. DOI: 10.1002/jcb.10432. View

Zhang Y, Staal B, Su Y, Swiatek P, Zhao P, Cao B . Evidence that MIG-6 is a tumor-suppressor gene. Oncogene. 2006; 26(2):269-76. DOI: 10.1038/sj.onc.1209790. View

Narvaez C, Byrne B, Romu S, Valrance M, Welsh J . Induction of apoptosis by 1,25-dihydroxyvitamin D3 in MCF-7 Vitamin D3-resistant variant can be sensitized by TPA. J Steroid Biochem Mol Biol. 2003; 84(2-3):199-209. DOI: 10.1016/s0960-0760(03)00029-3. View

Zanello L, Norman A . Rapid modulation of osteoblast ion channel responses by 1alpha,25(OH)2-vitamin D3 requires the presence of a functional vitamin D nuclear receptor. Proc Natl Acad Sci U S A. 2004; 101(6):1589-94. PMC: 341781. DOI: 10.1073/pnas.0305802101. View

Mordan-McCombs S, Brown T, Wang W, Gaupel A, Welsh J, Tenniswood M . Tumor progression in the LPB-Tag transgenic model of prostate cancer is altered by vitamin D receptor and serum testosterone status. J Steroid Biochem Mol Biol. 2010; 121(1-2):368-71. PMC: 4211603. DOI: 10.1016/j.jsbmb.2010.03.062. View

Azam N, Vairapandi M, Zhang W, Hoffman B, Liebermann D . Interaction of CR6 (GADD45gamma ) with proliferating cell nuclear antigen impedes negative growth control. J Biol Chem. 2000; 276(4):2766-74. DOI: 10.1074/jbc.M005626200. View

Mehrian-Shai R, Chen C, Shi T, Horvath S, Nelson S, Reichardt J . Insulin growth factor-binding protein 2 is a candidate biomarker for PTEN status and PI3K/Akt pathway activation in glioblastoma and prostate cancer. Proc Natl Acad Sci U S A. 2007; 104(13):5563-8. PMC: 1838515. DOI: 10.1073/pnas.0609139104. View

10.

Alagbala A, Moser M, Johnson C, Trump D, Foster B . Characterization of Vitamin D insensitive prostate cancer cells. J Steroid Biochem Mol Biol. 2007; 103(3-5):712-6. PMC: 1892312. DOI: 10.1016/j.jsbmb.2006.12.008. View

11.

Vairapandi M, Balliet A, Fornace Jr A, Hoffman B, Liebermann D . The differentiation primary response gene MyD118, related to GADD45, encodes for a nuclear protein which interacts with PCNA and p21WAF1/CIP1. Oncogene. 1996; 12(12):2579-94. View

12.

Chung I, Han G, Seshadri M, Gillard B, Yu W, Foster B . Role of vitamin D receptor in the antiproliferative effects of calcitriol in tumor-derived endothelial cells and tumor angiogenesis in vivo. Cancer Res. 2009; 69(3):967-75. PMC: 2752059. DOI: 10.1158/0008-5472.CAN-08-2307. View

13.

Debes J, Tindall D . The role of androgens and the androgen receptor in prostate cancer. Cancer Lett. 2002; 187(1-2):1-7. DOI: 10.1016/s0304-3835(02)00413-5. View

14.

Rohan J, Weigel N . 1Alpha,25-dihydroxyvitamin D3 reduces c-Myc expression, inhibiting proliferation and causing G1 accumulation in C4-2 prostate cancer cells. Endocrinology. 2009; 150(5):2046-54. PMC: 2671895. DOI: 10.1210/en.2008-1395. View

15.

Peng L, J Malloy P, Feldman D . Identification of a functional vitamin D response element in the human insulin-like growth factor binding protein-3 promoter. Mol Endocrinol. 2004; 18(5):1109-19. DOI: 10.1210/me.2003-0344. View

16.

Miyake Z, Takekawa M, Ge Q, Saito H . Activation of MTK1/MEKK4 by GADD45 through induced N-C dissociation and dimerization-mediated trans autophosphorylation of the MTK1 kinase domain. Mol Cell Biol. 2007; 27(7):2765-76. PMC: 1899887. DOI: 10.1128/MCB.01435-06. View

17.

Bao B, Ting H, Hsu J, Yasmin-Karim S, Messing E, Lee Y . Down-regulation of NF-kappaB signals is involved in loss of 1alpha,25-dihydroxyvitamin D3 responsiveness. J Steroid Biochem Mol Biol. 2010; 120(1):11-21. DOI: 10.1016/j.jsbmb.2010.02.030. View

18.

Zhuang S, Schwartz G, Cameron D, Burnstein K . Vitamin D receptor content and transcriptional activity do not fully predict antiproliferative effects of vitamin D in human prostate cancer cell lines. Mol Cell Endocrinol. 1997; 126(1):83-90. DOI: 10.1016/s0303-7207(96)03974-3. View

19.

Oades G, Dredge K, Kirby R, Colston K . Vitamin D receptor-dependent antitumour effects of 1,25-dihydroxyvitamin D3 and two synthetic analogues in three in vivo models of prostate cancer. BJU Int. 2002; 90(6):607-16. DOI: 10.1046/j.1464-410x.2002.02964.x. View

20.

Ferby I, Reschke M, Kudlacek O, Knyazev P, Pante G, Amann K . Mig6 is a negative regulator of EGF receptor-mediated skin morphogenesis and tumor formation. Nat Med. 2006; 12(5):568-73. DOI: 10.1038/nm1401. View