title: Epimorphin-induced MET sensitizes ovarian cancer cells to platinum.
abstract: Distinctive genotypic and phenotypic features of ovarian cancer via epithelial-mesenchymal transition (EMT) have been correlated with drug resistance and disease recurrence. We investigated whether therapeutic reversal of EMT could re-sensitize ovarian cancer cells (OCCs) to existing chemotherapy. We report that epimorphin, a morphogenic protein, has pivotal control over mesenchymal versus epithelial cell lineage decision of the putative OCCs. Exposure to epimorphin induced morphological changes reminiscent of mesenchymal-to-epithelial transition (MET), but in a dose dependent manner, i.e., at 10 µg/mL of epimorphin cells obtain a more mesenchymal-like morphology while at 20 µg/mL of epimorphin cells display an epithelial morphology. The latter changes were accompanied by suppression of mesenchymal markers, such as vimentin (∼8-fold↓, p<0.02), Twist1 (∼7-fold↓, p<0.03), dystroglycan (∼4-fold↓, p<0.01) and palladin (∼3-fold↓, p<0.01). Conversely, significant elevations of KLF4 (∼28-fold↑, p<0.002), β-catenin (∼6-fold↑, p<0.004), EpCAM (∼6-fold↑, p<0.0002) and occludin (∼15-fold↑, p<0.004) mRNAs as part of the commitment to the epithelial cell lineage were detected in response to 20 µg/mL of exogenous epimorphin. Changes in occludin mRNA levels were accompanied by a parallel, albeit weaker expression at the protein level (∼5-fold↑, p<0.001). Likewise, acquisition of epithelial-like properties, including mucin1, CK19, and β-catenin gene expression, was also obtained following epimorphin treatment. Further, MMP3 production was found to be reduced whereas laminin secretion was strongly amplified upon epimorphin-induced MET. These results suggest there is a dosage window for actions of epimorphin on cellular differentiation, wherein it can either suppress or enhance epithelial differentiation of OCCs. Importantly, induction of epithelial-like phenotypes by epimorphin led to an enhanced sensitivity to carboplatin. Overall, we demonstrate that epimorphin can revert OCCs away from their mesenchymal phenotype and toward an epithelial phenotype, thereby enhancing their sensitivity to a front-line chemotherapeutic agent.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, United States of America.
authors.forename: Kok-Hooi
authors.initials: KH
authors.lastname: Yew
authors.forename: Jennifer
authors.initials: J
authors.lastname: Crow
authors.forename: Jeff
authors.initials: J
authors.lastname: Hirst
authors.forename: Ziyan
authors.initials: Z
authors.lastname: Pessetto
authors.forename: Ziyan
authors.initials: Z
authors.lastname: Pressetto
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D016190:Carboplatin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D048430:Cell Shape; D002470:Cell Survival / Q000187:drug effects; D054338:Cell Transdifferentiation; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000090062:Kruppel-Like Factor 4; D007797:Laminin / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D010051:Ovarian Neoplasms; D010641:Phenotype; D050827:Syntaxin 1 / Q000502:physiology*; D059467:Transcriptome; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D007797:Laminin; C074558:STX2 protein, human; D050827:Syntaxin 1; D051176:beta Catenin; D016190:Carboplatin; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3
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