Progestins inhibit calcitriol-induced CYP24A1 and synergistically inhibit ovarian cancer cell viability: An opportunity for chemoprevention

Rodriguez, Gustavo C.; Turbov, Jane M.; Rosales, Rebecca; Yoo, Jennifer; Hunn, Jessica; Zappia, Katherine J.; Lund, Kaarin; Barry, Catherine P.; Rodriguez, Isabel V.; Pike, J. Wesley; Conrads, Thomas P.; Darcy, Kathleen M.; Maxwell, G. Larry; Hamilton, Chad A.; Syed, Viqar; Thaete, Larry G.

doi:10.1016/j.ygyno.2016.04.022

Cited by 27 publications

(25 citation statements)

References 40 publications

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“…In previous studies, we have shown that progesterone-calcitriol combination has cytotoxic and pro-apoptotic effects against ovarian and endometrial cancer cells in vitro [22][23][24][25]. In the present in vitro study, progesterone-calcitriol combination synergistically enhanced the anti-proliferative, cytotoxic, and pro-apoptotic effects of DDP compared to those cells treated with a single agent.…”

Section: Discussionsupporting

confidence: 61%

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Progesterone-Calcitriol Combination Enhanced Cytotoxicity of Cisplatin in Ovarian and Endometrial Cancer Cells In Vitro

et al. 2020

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Initially, patients that respond to cisplatin (DDP) treatment later relapse and develop chemoresistance. Agents that enhance DDP effectiveness will have a significant impact on cancer treatment. We have shown pronounced inhibitory effects of the progesterone-calcitriol combination on endometrial and ovarian cancer cell growth. Here, we examined whether and how progesterone-calcitriol combination potentiates DDP anti-tumor effects in cancer cells. Ovarian and endometrial cancer cells treated with various concentrations of DDP showed a concentration-dependent decrease in cell proliferation. Concurrent treatment of cells with DDP and progesterone-calcitriol ombination potentiated anticancer effects of DDP compared to DDP-calcitriol, or DDP-progesterone treated groups. The anticancer effects were mediated by increased caspase-3, BAX, and decreased BCL2 and PARP-1 expression in DDP and progesterone-calcitriol combination-treated cells. Stimulation of the PI3K/AKT and MAPK/ERK pathways seen in cancer cells was reduced in DDP-progesterone-calcitriol treated cells. Pretreatment of cells with specific inhibitors further diminished AKT and ERK expression. Furthermore, progesterone-calcitriol potentiated the anti-growth effects of DDP on cancer cells by attenuating the expression of SMAD2/3, multidrug resistance protein- 1 (MDR-1), and ABC transporters (ABCG1, and ABCG2), thereby impeding the efflux of chemo drugs from cancer cells. These results suggest a potential clinical benefit of progesterone-calcitriol combination therapy when used in combination with DDP.

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Section: Discussionsupporting

confidence: 61%

“…Earlier studies have shown that a combination of progesterone-calcitriol treatment synergistically inhibited the growth of endometrial and ovarian cancer cell lines [22][23][24][25]. To date, whether the progesterone-calcitriol combination can effectively promote efficacies of anticancer chemotherapeutics has not been explored.…”

Section: Introductionmentioning

confidence: 99%

Progesterone-Calcitriol Combination Enhanced Cytotoxicity of Cisplatin in Ovarian and Endometrial Cancer Cells In Vitro

et al. 2020

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“…Our previous studies have shown that progesterone and calcitriol inhibit ovarian and endometrial cancer growth through caspase-3 activation, induction of G 0 –G 1 cell-cycle arrest, downregulation of TGF-β, MMP-9 and MMP-2 signaling [ 27 , 28 , 29 , 30 ]. In the present study, we found a moderate (10–20%) decrease of MT1-MMP activity in calcitriol treated cells compared to vehicle treated cells.…”

Section: Discussionmentioning

confidence: 99%

“…In our previous studies, we have shown that combining progesterone with calcitriol have synergistic inhibitory effects on growth of endometrial and ovarian cancer cells [ 27 – 30 ]. The aim of the present study is to evaluate whether the combination of progesterone with calcitriol exerted antitumor effects on invasion and metastasis of human endometrial cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Progesterone and calcitriol reduce invasive potential of endometrial cancer cells by targeting ARF6, NEDD9 and MT1-MMP

et al. 2017

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Previously, we have demonstrated that progesterone and calcitriol synergistically inhibit growth of endometrial and ovarian cancer by enhancing apoptosis and causing cell cycle arrest. Metastasis is the main reason of mortality in cancer patients. Activation of ADP-Ribosylation Factor 6 (ARF6), Neural Precursor cell expressed Developmentally Downregulated 9 (NEDD9), and Membrane-Type-1 Matrix Metalloproteinase (MT1-MMP) have been implicated in promoting tumor growth and metastasis. We examined the effects of progesterone, calcitriol and progesterone-calcitriol combination on metastasis promoting proteins in endometrial cancer. Expression of ARF6, NEDD9, and MT1-MMP was enhanced in advanced-stage endometrial tumors and in cancer cell lines compared to normal tissues and immortalized EM-E6/E7-TERT endometrial epithelial cells. Knockdown of these proteins significantly inhibited the invasiveness of the cancer cells. The expression levels of all three proteins was reduced with progesterone and progesterone-calcitriol combination treatment, whereas calcitriol alone showed no effect on their expression but moderately decreased MT1-MMP activity. Fluorescence microscopy showed membrane expression of MT1-MMP in vehicle and calcitriol-treated endometrial cancer cells. However, progesterone and calcitriol-progesterone combination treatment revealed MT1-MMP in the cytoplasm. Furthermore, progesterone and calcitriol reduced the activity of MT1-MMP, MMP-9, and MMP-2. In addition, invadopodia regulatory proteins were attenuated in both progesterone and progesterone-calcitriol combination treated cells as well as in MT1-MMP knockdown cells. Thus, targeting the aberrant MT1-MMP signaling with progesterone-calcitriol may be a novel approach to impede MT1-MMP mediated cancer dissemination and may have therapeutic benefits for endometrial cancer patients.

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“…Solar ultraviolet-B (UVB) irradiation increases the serum vitamin D level in humans [21,22], suggesting that vitamin D may have protective effect against ovarian cancer. Calcitriol (1,25-dihydroxycholecaldiferol, 1,25(OH) 2 D 3 ), the active form of vitamin D, exerts antineoplastic effects in colorectal cancer [23], prostate cancer [24,25], ovarian cancer [26,27] and breast cancer [28]. A Phase II trial of the combinational therapy with calcitriol and anti-inflammatory drugs [29,30] (such as naproxen and dexamethasone) showed antitumor activities in prostate cancer patients with safety and well tolerance.…”

Section: Introductionmentioning

confidence: 99%

Vitamin D Suppresses Ovarian Cancer Growth and Invasion by Targeting Long Non-Coding RNA CCAT2

Wang

Zhou

Guo

2020

IJMS

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Ovarian cancer is the most deadly gynecologic cancer among women worldwide. Poor response to current treatment makes it necessary to discover new diagnostic biomarkers to detect the cancer early and develop new and effective prevention strategies. Calcitriol, the active metabolite of vitamin D, protects against multiple cancers through unelucidated mechanisms. The oncogenic long non-coding RNA (lncRNA) CCAT2 (colon cancer associated transcript 2) is overexpressed in ovarian cancer. Here, we foundd that calcitriol inhibited CCAT2 expression in ovarian cancer cell lines. Treatment with calcitriol inhibited ovarian cancer cell proliferation, migration, and invasion. As a result of CCAT2 inhibition, calcitriol decreased the binding of transcription factor TCF7L2 (TCF4) to the MYC promoter, resulting in the repression of c-Myc protein expression. Our results suggest a novel anti-cancer mechanism of vitamin D by targeting CCAT2 in ovarian cancer. The findings may help develop vitamin D as a practical and inexpensive nutraceutical for ovarian cancer prevention.

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Progestins inhibit calcitriol-induced CYP24A1 and synergistically inhibit ovarian cancer cell viability: An opportunity for chemoprevention

Cited by 27 publications

References 40 publications

Progesterone-Calcitriol Combination Enhanced Cytotoxicity of Cisplatin in Ovarian and Endometrial Cancer Cells In Vitro

Progesterone-Calcitriol Combination Enhanced Cytotoxicity of Cisplatin in Ovarian and Endometrial Cancer Cells In Vitro

Progesterone and calcitriol reduce invasive potential of endometrial cancer cells by targeting ARF6, NEDD9 and MT1-MMP

Vitamin D Suppresses Ovarian Cancer Growth and Invasion by Targeting Long Non-Coding RNA CCAT2

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