Progesterone and calcitriol reduce invasive potential of endometrial cancer cells by targeting ARF6, NEDD9 and MT1-MMP
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Sana Waheed1, Batsukh Dorjbal1, Chad A. Hamilton1,2,3, G. Larry Maxwell2,3,4, Gustavo C. Rodriguez5 and Viqar Syed1,3,6
1Uniformed Services University, Department of Obstetrics and Gynecology, Bethesda, MD 20814, USA
2Women’s Health Integrated Research Center at Inova Health System, Department of Defense Gynecologic Cancer Center of Excellence, Annandale, VA 22003, USA
3John P. Murtha Cancer Center at Water Reed National Military Medical Center, Bethesda, MD 20889, USA
4Inova Fairfax Hospital, Department of Obstetrics and Gynecology, Falls Church, VA 22042, USA
5Division of Gynecologic Oncology, North Shore University Health-System, University of Chicago, Evanston, IL 60201, USA
6Uniformed Services University, Department of Molecular and Cell Biology, Bethesda, MD 20814, USA
Viqar Syed, email: [email protected]
Keywords: migration; invasion; matrix metalloproteinases; invadopodia; membrane trafficking
Received: August 23, 2017 Accepted: November 05, 2017 Published: November 28, 2017
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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