title: Progesterone and calcitriol attenuate inflammatory cytokines CXCL1 and CXCL2 in ovarian and endometrial cancer cells.
abstract: Cytokines/chemokines are key players in cancer-related inflammation. Increasing evidence suggests that chemokines produced by tumor cells are the mediators of metastasis. Thus, agents that can downregulate chemokines expression have potential against cancer metastasis. We have previously shown inhibition of ovarian and endometrial cancer cell growth with progesterone and calcitriol. In the present study, we evaluated the effect of these two agents on the expression of inflammatory genes. Using a RT-PCR array of inflammatory cytokines/chemokines and their receptors, we found a marked attenuation of CXCL1 and CXCL2 (GRO-α and -β) in cancer cells by both treatments. Knockdown of NFκB resulted in a reduced expression of CXCL1 and CXCL2 and the inhibitory effect of progesterone and calcitriol on the expression of chemokines was abrogated in NFκB-silenced cancer cells. Silencing of IκBα increased the expression of CXCL1 and CXCL2 in cancer cells, which can be attributed to the increased activation of NFκB-p65, caused by the lack of its inhibitor. Progesterone and calcitriol-induced inhibition was abolished in IκBα-knockdown cells. Our results demonstrate that suppression of IκBα phosphorylation by progesterone and calcitriol contributes to the reduced expression of CXCL1 and CXCL2. Downregulation of CXCL1 and CXCL2 was associated with a marked inhibition of metastasis-promoting genes. Overall, our results indicate that progesterone and calcitriol inhibit IκBα phosphorylation, NFκB activation, and the expression of NFκB regulated metastasis promoting genes. These results provide attractive data for the possible use of progesterone and calcitriol in the management of endometrial and ovarian tumors.
authors.affiliation: Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
authors.forename: Leyla
authors.initials: L
authors.lastname: Kavandi
authors.forename: Michael A
authors.initials: MA
authors.lastname: Collier
authors.forename: Huyen
authors.initials: H
authors.lastname: Nguyen
authors.forename: Viqar
authors.initials: V
authors.lastname: Syed
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002117:Calcitriol / Q000494:pharmacology*; D045744:Cell Line, Tumor; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism*; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D009362:Neoplasm Metastasis / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D011374:Progesterone / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; C475829:CXCL1 protein, human; C499706:CXCL2 protein, human; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D011374:Progesterone; D002117:Calcitriol