Inhibition of CYP27B1 and CYP24 Increases the Anti-proliferative Effects of 25-Hydroxyvitamin D₃ in LNCaP Cells

Abstract

Background/Aim: Growing evidence suggests that vitamin D 3 exerts anticancer effects. The present study aimed to evaluate 25-hydroxyvitamin D 3 (25(OH)D 3 ) as a potential endocrine factor regulating proliferation and vitamin D receptor expression in LNCaP prostate cancer cells. Materials and Methods: Cell counting after treatment was utilized to assess the effect of 25(OH)D 3 on cell proliferation. Changes in mRNA expression of the vitamin D receptors, VDR and PDIA3, were evaluated using droplet digital polymerase chain reaction (ddPCR). Results: 25(OH)D 3 inhibited cell proliferation in a dose-and time-dependent manner. The inhibitory effect of 25(OH)D 3 on cell proliferation was potentiated after inhibition of CYP17B1 and CYP24 by genistein, preventing further metabolism of 25(OH)D 3 to 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) and 24,25-dihydroxyvitamin D 3 (24,25(OH) 2 D 3 ). Expression of PDIA3 and VDR mRNA increased after treatment with 25(OH)D 3 , whereas the ratio between PDIA3 and VDR mRNA remained unchanged. Conclusion: 25(OH)D 3 has a direct inhibitory effect on cell proliferation, which is enhanced and accelerated when the metabolism of 25(OH)D 3 to 1,25(OH) 2 D 3 and 24,25(OH) 2 D 3 was inhibited by the CYP17B1 and CYP24 inhibitor genistein. Furthermore, treatment with 25(OH)D 3 increased receptor transcript expression, suggesting an increased VDR stability and sensibility of the treated cells.

Serum Vitamin D Level Status by Prostate Cancer Grade and Stage Among Native Africans

“…The repression of these vital intra-prostatic functions of Vitamin D, occasioned by its deficiency status, is the cardinal initiating event in PCa adverse pathology (worsening grade/stage) observed in the current study [30][31][32][33][34][35][36][37]. The Vitamin D-induced cell cycle arrest/apoptotic effect is mediated via down-regulation of the anti-apoptotic proteins (Bcl-2, Bcl-XL) and up-regulation of pro-apoptotic proteins (Bax, Bak, Bad) [30][31][32][33]. The antiinflammatory effects are mediated through the inhibitions of prostaglandin synthesis, p38-MAPK signaling, NF-Kb, and modulation of immune-cancer cell interaction [34,35].…”

“…The various anti-PCa properties of Vitamin D are orchestrated via the actions of 1,25(OH)D (calcitriol) on VDR within the normal prostate cells and the tumor microenvironment [30][31][32][33][34][35][36][37]. These actions are generally thought to be mediated mainly through Vitamin D-induced cell growth arrest and enhancement of apoptosis but other potential mechanisms also play vital roles [30].…”

“…These actions are generally thought to be mediated mainly through Vitamin D-induced cell growth arrest and enhancement of apoptosis but other potential mechanisms also play vital roles [30]. The active Vitamin D also has anti-inflammatory effects, anti-oxidant/DNA damage repair effects, autophagic cell growth promotion, antiproliferative/pro-differentiating potentials, and antiangiogenic effects [31][32][33][34][35][36][37][38]. The repression of these vital intra-prostatic functions of Vitamin D, occasioned by its deficiency status, is the cardinal initiating event in PCa adverse pathology (worsening grade/stage) observed in the current study [30][31][32][33][34][35][36][37].…”

“…The active Vitamin D also has anti-inflammatory effects, anti-oxidant/DNA damage repair effects, autophagic cell growth promotion, antiproliferative/pro-differentiating potentials, and antiangiogenic effects [31][32][33][34][35][36][37][38]. The repression of these vital intra-prostatic functions of Vitamin D, occasioned by its deficiency status, is the cardinal initiating event in PCa adverse pathology (worsening grade/stage) observed in the current study [30][31][32][33][34][35][36][37]. The Vitamin D-induced cell cycle arrest/apoptotic effect is mediated via down-regulation of the anti-apoptotic proteins (Bcl-2, Bcl-XL) and up-regulation of pro-apoptotic proteins (Bax, Bak, Bad) [30][31][32][33].…”

“…Promotion of autophagic cell death is achieved via a switch from cell survival to cell death and the up-regulation of Beclin 1 and the suppression of mTORC1 [34,35]. The anti-proliferative/pro-differentiating potentials of active Vitamin D are mediated by up-regulating the CDK inhibitors (p21, p27) and the inhibition of Wnt/β-catenin signaling and telomerase activities [32,37].…”