title: Verteporfin exhibits YAP-independent anti-proliferative and cytotoxic effects in endometrial cancer cells.
abstract: Endometrial Carcinoma (EMCA) is the most common gynecologic malignancy and the fourth most common malignancy in women in the United States. Yes-associated protein (YAP) is a potent transcription coactivator acting via binding to the TEAD transcription factor, and plays a critical role in organ size regulation. Verteporfin (VP), a benzoporphyrin derivative, was identified as an inhibitor of YAP-TEAD interaction. We investigated the therapeutic efficacy and mechanism of VP in EMCA. The efficacy of VP on cell viability, cytotoxicity and invasion was assayed in EMCA cell lines. An organoid model system was also developed to test the effect of VP on apoptotic markers in an in vitro model system. Treatment with VP resulted in a decrease in cell viability, invasion and an increase in cytotoxicity of EMCA cells. These effects occurred as early as 15 minutes following treatment. Similarly, VP treatment versus vehicle control increased apoptosis in human organoid model systems. Quantitative RT-PCR, cDNA based RTPCR array analysis and western blotting were performed to investigate the mechanism of VP action. The cytotoxic and anti-proliferative effects appeared to be independent of its effect on YAP. Our results suggest that VP is a promising chemotherapeutic agent for the treatment of endometrial cancer.
authors.affiliation: Weis Center for Research, Geisinger Medical Center, Danville, PA, USA.
authors.forename: Venkata Ramesh
authors.initials: VR
authors.lastname: Dasari
authors.affiliation: Weis Center for Research, Geisinger Medical Center, Danville, PA, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Mazack
authors.affiliation: Henry Hood Center for Health Research, Geisinger Medical Center, Danville, PA, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Feng
authors.affiliation: Weis Center for Research, Geisinger Medical Center, Danville, PA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Nash
authors.affiliation: Weis Center for Research, Geisinger Medical Center, Danville, PA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Carey
authors.affiliation: Weis Center for Research, Geisinger Medical Center, Danville, PA, USA.
authors.forename: Radhika
authors.initials: R
authors.lastname: Gogoi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism*; D005260:Female; D000090683:Hippo Signaling Pathway; D006801:Humans; D010750:Phosphoproteins / Q000378:metabolism*; D011166:Porphyrins / Q000494:pharmacology*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors; D000077362:Verteporfin; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D010750:Phosphoproteins; D011166:Porphyrins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000077362:Verteporfin; D017346:Protein Serine-Threonine Kinases
keywords: YAP; endometrial carcinoma; hippo pathway; organoids; verteporfin