PTHrP contributes to the anti-proliferative and integrin α6β4-regulating effects of 1,25-dihydroxyvitamin D3

Xiaoli Shen, Ramanjaneya V R Mula, Jing Li, Nancy L. Weigel, Miriam Falzon

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Parathyroid hormone-related protein (PTHrP) increases the growth and metastatic potential of prostate cancer cells, making it important to control PTHrP expression in these cells. 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] suppresses PTHrP expression and exerts an anti-proliferative effect in prostate carcinoma cells. We used the human prostate cancer cell line C4-2 as a model system to ask whether down-regulation of PTHrP expression by 1,25(OH)2D3 plays a role in the anti-proliferative effects of 1,25(OH)2D3. Since PTHrP increases the expression of the pro-invasive integrin α6β4, we also asked whether 1,25(OH)2D3 decreases integrin α6β4 expression in C4-2 cells, and whether modulation of PTHrP expression by 1,25(OH)2D3 plays a role in the effects of 1,25(OH)2D3 on integrin α6β4 expression. Two strategies were utilized to modulate PTHrP levels: overexpression of PTHrP (-36 to +139) and suppression of endogenous PTHrP expression using siRNAs. We report a direct correlation between PTHrP expression, C4-2 cell proliferation and integrin α6β4 expression at the mRNA and cell surface protein level. Treatment of parental C4-2 cells with 1,25(OH)2D3 decreased cell proliferation and integrin α6 and β4 expression. These 1,25(OH)2D3 effects were significantly attenuated in cells with suppressed PTHrP expression. 1,25(OH)2D3 regulates PTHrP expression via a negative vitamin D response element (nVDRE) within the noncoding region of the PTHrP gene. The effects of 1,25(OH)2D3 on cell proliferation and integrin α6β4 expression were significantly attenuated in cells overexpressing PTHrP (-36 to +139), which lacks the nVDRE. These findings suggest that one of the pathways via which 1,25(OH)2D3 exerts its anti-proliferative effects is through down-regulation of PTHrP expression.

Original languageEnglish (US)
Pages (from-to)930-938
Number of pages9
JournalSteroids
Volume72
Issue number14
DOIs
StatePublished - Dec 2007

Fingerprint

Parathyroid Hormone-Related Protein
Calcitriol
Integrins
Vitamin D Response Element
Cell proliferation
Cells
Cell Proliferation
Prostatic Neoplasms
Down-Regulation

Keywords

  • 1,25-Dihydroxyvitamin D
  • Integrin α6β4
  • Prostate cancer
  • PTHrP

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Molecular Biology

Cite this

PTHrP contributes to the anti-proliferative and integrin α6β4-regulating effects of 1,25-dihydroxyvitamin D3 . / Shen, Xiaoli; Mula, Ramanjaneya V R; Li, Jing; Weigel, Nancy L.; Falzon, Miriam.

In: Steroids, Vol. 72, No. 14, 12.2007, p. 930-938.

Research output: Contribution to journalArticle

Shen, Xiaoli ; Mula, Ramanjaneya V R ; Li, Jing ; Weigel, Nancy L. ; Falzon, Miriam. / PTHrP contributes to the anti-proliferative and integrin α6β4-regulating effects of 1,25-dihydroxyvitamin D3 In: Steroids. 2007 ; Vol. 72, No. 14. pp. 930-938.
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abstract = "Parathyroid hormone-related protein (PTHrP) increases the growth and metastatic potential of prostate cancer cells, making it important to control PTHrP expression in these cells. 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] suppresses PTHrP expression and exerts an anti-proliferative effect in prostate carcinoma cells. We used the human prostate cancer cell line C4-2 as a model system to ask whether down-regulation of PTHrP expression by 1,25(OH)2D3 plays a role in the anti-proliferative effects of 1,25(OH)2D3. Since PTHrP increases the expression of the pro-invasive integrin α6β4, we also asked whether 1,25(OH)2D3 decreases integrin α6β4 expression in C4-2 cells, and whether modulation of PTHrP expression by 1,25(OH)2D3 plays a role in the effects of 1,25(OH)2D3 on integrin α6β4 expression. Two strategies were utilized to modulate PTHrP levels: overexpression of PTHrP (-36 to +139) and suppression of endogenous PTHrP expression using siRNAs. We report a direct correlation between PTHrP expression, C4-2 cell proliferation and integrin α6β4 expression at the mRNA and cell surface protein level. Treatment of parental C4-2 cells with 1,25(OH)2D3 decreased cell proliferation and integrin α6 and β4 expression. These 1,25(OH)2D3 effects were significantly attenuated in cells with suppressed PTHrP expression. 1,25(OH)2D3 regulates PTHrP expression via a negative vitamin D response element (nVDRE) within the noncoding region of the PTHrP gene. The effects of 1,25(OH)2D3 on cell proliferation and integrin α6β4 expression were significantly attenuated in cells overexpressing PTHrP (-36 to +139), which lacks the nVDRE. These findings suggest that one of the pathways via which 1,25(OH)2D3 exerts its anti-proliferative effects is through down-regulation of PTHrP expression.",
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AU - Mula, Ramanjaneya V R

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AU - Weigel, Nancy L.

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N2 - Parathyroid hormone-related protein (PTHrP) increases the growth and metastatic potential of prostate cancer cells, making it important to control PTHrP expression in these cells. 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] suppresses PTHrP expression and exerts an anti-proliferative effect in prostate carcinoma cells. We used the human prostate cancer cell line C4-2 as a model system to ask whether down-regulation of PTHrP expression by 1,25(OH)2D3 plays a role in the anti-proliferative effects of 1,25(OH)2D3. Since PTHrP increases the expression of the pro-invasive integrin α6β4, we also asked whether 1,25(OH)2D3 decreases integrin α6β4 expression in C4-2 cells, and whether modulation of PTHrP expression by 1,25(OH)2D3 plays a role in the effects of 1,25(OH)2D3 on integrin α6β4 expression. Two strategies were utilized to modulate PTHrP levels: overexpression of PTHrP (-36 to +139) and suppression of endogenous PTHrP expression using siRNAs. We report a direct correlation between PTHrP expression, C4-2 cell proliferation and integrin α6β4 expression at the mRNA and cell surface protein level. Treatment of parental C4-2 cells with 1,25(OH)2D3 decreased cell proliferation and integrin α6 and β4 expression. These 1,25(OH)2D3 effects were significantly attenuated in cells with suppressed PTHrP expression. 1,25(OH)2D3 regulates PTHrP expression via a negative vitamin D response element (nVDRE) within the noncoding region of the PTHrP gene. The effects of 1,25(OH)2D3 on cell proliferation and integrin α6β4 expression were significantly attenuated in cells overexpressing PTHrP (-36 to +139), which lacks the nVDRE. These findings suggest that one of the pathways via which 1,25(OH)2D3 exerts its anti-proliferative effects is through down-regulation of PTHrP expression.

AB - Parathyroid hormone-related protein (PTHrP) increases the growth and metastatic potential of prostate cancer cells, making it important to control PTHrP expression in these cells. 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] suppresses PTHrP expression and exerts an anti-proliferative effect in prostate carcinoma cells. We used the human prostate cancer cell line C4-2 as a model system to ask whether down-regulation of PTHrP expression by 1,25(OH)2D3 plays a role in the anti-proliferative effects of 1,25(OH)2D3. Since PTHrP increases the expression of the pro-invasive integrin α6β4, we also asked whether 1,25(OH)2D3 decreases integrin α6β4 expression in C4-2 cells, and whether modulation of PTHrP expression by 1,25(OH)2D3 plays a role in the effects of 1,25(OH)2D3 on integrin α6β4 expression. Two strategies were utilized to modulate PTHrP levels: overexpression of PTHrP (-36 to +139) and suppression of endogenous PTHrP expression using siRNAs. We report a direct correlation between PTHrP expression, C4-2 cell proliferation and integrin α6β4 expression at the mRNA and cell surface protein level. Treatment of parental C4-2 cells with 1,25(OH)2D3 decreased cell proliferation and integrin α6 and β4 expression. These 1,25(OH)2D3 effects were significantly attenuated in cells with suppressed PTHrP expression. 1,25(OH)2D3 regulates PTHrP expression via a negative vitamin D response element (nVDRE) within the noncoding region of the PTHrP gene. The effects of 1,25(OH)2D3 on cell proliferation and integrin α6β4 expression were significantly attenuated in cells overexpressing PTHrP (-36 to +139), which lacks the nVDRE. These findings suggest that one of the pathways via which 1,25(OH)2D3 exerts its anti-proliferative effects is through down-regulation of PTHrP expression.

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