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TGF-Β Signaling Proteins and CYP24A1 May Serve As Surrogate

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TGF-Β Signaling Proteins and CYP24A1 May Serve As Surrogate 1437 Original Article TGF-β signaling proteins and CYP24A1 may serve as surrogate markers for progesterone calcitriol treatment in ovarian and endometrial cancers of different histological types Ana Paucarmayta1, Hannah Taitz1, Yovanni Casablanca1,2,3, Gustavo C. Rodriguez4, G. Larry Maxwell2,3,5, Kathleen M. Darcy2,3,6, Viqar Syed1,3,7 1Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA; 2Gynecologic Cancer Center of Excellence, 3John P. Murtha Cancer Center, Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences and Walter Reed National Military Medical Center, Bethesda, MD, USA; 4Division of Gynecologic Oncology, NorthShore University HealthSystem, University of Chicago, Evanston, IL, USA; 5Department of Obstetrics and Gynecology, Inova Fairfax Hospital, Falls Church, VA, USA; 6Inova Schar Cancer Institute, Inova Center for Personalized Health, Falls Church, VA, USA; 7Department of Molecular and Cell Biology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA Contributions: (I) Conception and design: KM Darcy, GL Maxwell, V Syed; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: A Paucarmayta, H Taitz, V Syed; (V) Data analysis and interpretation: A Paucarmayta, H Taitz, KM Darcy, V Syed; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Viqar Syed. John P. Murtha Cancer Center, Department of Obstetrics and Gynecology, Department of Molecular and Cell Biology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Room# A-3080, Bethesda, MD, USA. Email: [email protected]. Background: Strategies are needed to coordinately block drivers and induce suppressors of cancer to reduce incidence and improve outcomes for individuals with inherited or acquired risk. We previously reported the chemopreventive and therapeutic efficacy of the combination of progestin and calcitriol in transformed and malignant endometrioid endometrial cancer (EC) and in ovarian cancer models involving attenuated expression of TGF-β signaling proteins and progestin-mediated inhibition of calcitriol-induced CYP24A1 expression. This study aims to expand the applications for this combination to other subtypes of endometrial and ovarian cancers, including those with mutations in ARID1A or PIK3CA, DNA mismatch repair (MMR) deficiency or BRCA1 null status. Methods: Ovarian and EC cell lines of different histotypes were cultured with either progesterone, calcitriol, or the combination of progesterone and calcitriol for 3 or 5 days. The end points for this in vitro investigation included assessments of cell growth by (3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assays and the expression of TGF-β ligands, receptors, SMAD proteins and CYP24A1 by western blotting. Results: Treatment of ovarian clear cell carcinoma, endometrioid carcinoma, papillary serous adenocarcinoma, BRCA1 null, and DNA MMR deficient EC cell lines with progesterone alone or in combination with calcitriol inhibited cell growth and expression of TGF-β1, TGF-β2, TGF-Rβ1, TGF-βR2, pSMAD2/3 and CYP24A1. Expression of TGF-βR3, SMAD-4, progesterone receptor (PR) and vitamin-D receptor (VDR) was not altered in any cell line tested except, ES-2, where VDR expression was upregulated in response to treatment. Conclusions: These results suggest that progesterone alone and progesterone-calcitriol combination have broad application in both chemopreventive and therapeutic settings that merit further development in a wide variety of ovarian and ECs, including those derived from germline or somatic mechanisms. Moreover, our data suggest that TGF-β signaling proteins and CYP24A1 may be effective surrogate markers indicative of treatment response. © Translational Cancer Research. All rights reserved. Transl Cancer Res 2019;8(4):1423-1437 | http://dx.doi.org/10.21037/tcr.2019.07.36 1424 Paucarmayta et al. Treatment response markers in ovarian and ECs Keywords: Cell proliferation; gynecological cancer, treatment markers, cancer subtypes, chemoprevention Submitted Mar 11, 2019. Accepted for publication Jul 09, 2019. doi: 10.21037/tcr.2019.07.36 View this article at: http://dx.doi.org/10.21037/tcr.2019.07.36 Introduction demonstrated a marked reduction of CYP24A1 expression in progesterone treated endometrial and ovarian cancer Endometrial cancer (EC) is the fifth most common type cells. These findings imply that CYP24A1 overexpression of cancer in developed countries. In 2019, there will diminishes the antitumor effects of calcitriol in cancer be approximately 320,000 new cases of EC worldwide, cells and that progestins can be promising for sustaining leading to 76,000 deaths (1). Uterine cancers are generally calcitriol’s anti-cancer activity (14,15). treated with surgery, radiation, hor monal therapy, and/or In a recent study, we examined the effects of chemotherapy contingent on stage and cancer type. Surgery progesterone, calcitriol, and their combination of EC is employed to treat patients with early stage disease (stages cells and identified their targets of action. Our results I and II). Approximately 28% of early stage patients have demonstrated that combination treatment of EC cells high-risk disease and also receive radiation and/or chemo- with both agents impeded cell proliferation through therapy in addition to surgery. Among the women with advanced-stage disease (stage III and IV), the majority increased vitamin-D receptor (VDR) expression, caspase-3 receive surgery followed by radiation and/or chemotherapy. activation, induction of cell-cycle arrest and downregulation Despite the success of primary treatment, nearly all of cyclins (16) TGF-β signaling pathway performs women with advanced disease experience a recurrence of important roles in several biological processes, such as cancer, which is often resistant to chemotherapy (2). The cell growth, differentiation, apoptosis and migration. unpretentious performance of therapeutic tactics has offered The TGF-β pathway is dysregulated in tumors and the impetus for the prevention of EC, a viable alternative to associated with cancer initiation and progression (17-19). chemotherapy. Bokhari et al. (20) reported a significant decrease in the A compelling body of clinical and epidemiologic expression of three TGFβ isoforms, TGF-β receptor and evidence suggests that progestins and vitamin-D are highly SMAD2/3 in progesterone treated EC cells. Additionally, effective cancer preventive agents. In premenopausal progesterone effectively reduced basal and TGF β1- women, progestin containing oral contraceptives use grants stimulated cancer cell viability and invasion, which was a significant reduction in cancer risk (3-5). Moreover, associated with increased E-cadherin and decreased progestin-potent oral contraceptives have increased vimentin expression. An inhibitor of TGFβRI blocked cancer protective effects compared to oral contraceptives TGFβ1-induced effects on cell viability and invasion and containing weak progestins (6,7). The active form of vitamin attenuated antitumor effects of progesterone. D3-calcitriol, produced in the epidermis or obtained from Previously, we have shown that the progesterone and the diet is known for the prevention of a number of tumors, calcitriol combination is highly effective in inhibiting including ovarian and ECs (8,9). Levels of vitamin-D are the growth of serous ovarian and endometrial tumors maintained by a number of enzymes that are involved in (14-16,20) by attenuating the expression of TGF-β the synthesis, activation and inactivation (10). The active signaling proteins and downregulating the expression of 1,25-D3 is neutralized by CYP24A1. This enzyme is vital vitamin-D inactivating enzyme, CYP24A1. There is a in determining the antitumor activity of vitamin-D3. It has critical need for developing effective chemopreventive been shown that high expression of CYP24A1 promotes and therapeutic strategies for distinct types of endometrial carcinogenesis in a number of cancers, including breast, and ovarian cancer, and to determine if a consistent set of thyroid and prostate (11-13). We compared the expression biomarkers may exist for evaluating the effectiveness of of CYP24A1 in endometrial and ovarian cancer cells treatments initially in preclinical models and ultimately and in immortalized endometrial and ovarian epithelial in investigations in human subjects. The availability of cells, and found elevated CYP24A1 expression in cancer a breadth of cancer cell lines from different subtypes cells compared to normal cells. Furthermore, our data provides opportunities for the design of cancer prevention/ © Translational Cancer Research. All rights reserved. Transl Cancer Res 2019;8(4):1423-1437 | http://dx.doi.org/10.21037/tcr.2019.07.36 Translational Cancer Research, Vol 8, No 4 August 2019 1425 treatment studies that can test the specificity or conversely, (10–80 nmol/L) or a combination for 72 or 120 hours. broad applicability of therapeutic interventions in the To avoid the toxicity associated with higher doses of clinic (21). The first goal of this study was to determine if progesterone in most experiments, we used the lower dose the progesterone and calcitriol combination have restricted of progesterone (20 μmol/L) that has a potent inhibitory or broad potential applications in chemoprevention
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