PPARγ Modulation of Cytokine-Stimulated MUC16 (CA125) Expression in Breast and Ovarian Cancer-Derived Cells.
CA125 is serum tumor marker consisting of an epitope carried by a portion of the extremely large (>3 MDa), heavily glycosylated cell surface transmembrane mucin, MUC16. In malignancies, membrane bound mucins lose their polarized distribution, become aberrantly over-expressed and protect tumor cells from the actions of chemotherapeutic agents as well as the immune system. Previously, we described stimulation of MUC16 expression by the proinflammatory cytokines, tumor necrosis factor α (TNFα) and interferon γ (IFNγ), in breast and ovarian cancer cells and tissues. Herein, we show that PPARγ modulates cytokine-stimulated MUC16 in a complex manner: at low concentrations (<10 µM) rosiglitazone further potentiates cytokine-driven MUC16 expression while at high concentrations (>20 µM) rosiglitazone antagonizes cytokine stimulation. Rosiglitazone actions were fully reversible by the PPARγ antagonist, GW9662. Furthermore, siRNA-mediated PPARγ knockdown also prevented a large portion of high dose rosiglitazone suppression of MUC16 expression indicating that rosiglitazone inhibition is largely PPARγ-dependent. Cytokines greatly (>75%) suppressed PPARγ expression. Conversely, PPARγ activation by rosiglitazone at either low or high concentrations greatly (>75%) suppressed NFκB/p65 expression. NFκB/p65 expression was largely preserved in the presence of cytokines at low, but not high, rosiglitazone concentrations accounting for the different concentration dependent effects on MUC16 expression. Collectively, these studies demonstrate that PPARγ is an important modulator of MUC16 expression. The ability to deliver high doses of PPARγ agonists to MUC16-expressing tumors offers an avenue to reduce expression of this protective glycoprotein and increase tumor sensitivity to killing by chemotherapeutic drugs and the immune system. J. Cell. Biochem. 118: 163-171, 2017. © 2016 Wiley Periodicals, Inc.
Department of BioSciences, Wiess School of Natural Sciences, Rice University, Houston 77251, Texas.
Micaela
M
Morgado
Department of BioSciences, Wiess School of Natural Sciences, Rice University, Houston 77251, Texas.|Department of Genetics, The University of Texas MD Anderson Cancer Center Houston, Houston 77030, Texas.
Daniel D
DD
Carson
D000813:Anilides / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D018394:CA-125 Antigen / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D018394:CA-125 Antigen; C573415:IFNG protein, human; C451759:MUC16 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D047495:PPAR gamma; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D007371:Interferon-gamma
CANCER; MUC16; PPARγ; ROSIGLITAZONE