GADD45γ: A new vitamin D-regulated gene that is antiproliferative in prostate cancer cells

Omar Flores, Kerry L Burnstein

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 G 1 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.

Original languageEnglish
Pages (from-to)4654-4664
Number of pages11
JournalEndocrinology
Volume151
Issue number10
DOIs
StatePublished - Oct 1 2010

Fingerprint

Vitamin D
Prostatic Neoplasms
Calcitriol Receptors
Genes
Androgen Receptors
Growth
Mitogens
Androgens
Cell Cycle
Up-Regulation
Calcitriol
Gene Expression Profiling
S Phase
DNA Damage
Prostate
Epithelial Cells
Cell Proliferation
Gene Expression
Cell Line
Ectopic Gene Expression

ASJC Scopus subject areas

  • Endocrinology

Cite this

GADD45γ : A new vitamin D-regulated gene that is antiproliferative in prostate cancer cells. / Flores, Omar; Burnstein, Kerry L.

In: Endocrinology, Vol. 151, No. 10, 01.10.2010, p. 4654-4664.

Research output: Contribution to journalArticle

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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 G 1 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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