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.

Retracted: p62 as a therapeutic target for inhibition of autophagy in prostate cancer

“…It has been reported that Verteporfin inhibited the interaction of YAP with TEAD, which, in turn, blocked transcriptional activation of target downstream of YAP, resulting in suppression of proliferation of several types of cancer cells 38 and tumor growth of PC-3 cells. 39 In contrast, other studies have indicated that inhibition of cell proliferation by Verteporfin in endometrial cancer cells 40 and colorectal cancer cells 41 are independent on YAP1. Our results suggest that inhibition of p62, Nrf2, Bcl-2, and Bcl-xL in PC-3 cells by…”

YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy

“…Histological staining of tumors and experiments in cancer cell lines have implicated YAP/TAZ in several other solid tumor types, including ovarian, [ 120–127 ] prostate, [ 128–134 ] bladder, [ 135–139 ] endometrial, [ 140,141 ] kidney, [ 142–144 ] thyroid, [ 145–149 ] adrenal, [ 150 ] mesothelioma, [ 151,152 ] sarcomas, [ 153–156 ] and epithelioid hemangioendothelioma. [ 157,158 ] In all the above cases, genetically engineered mouse models are still necessary to establish the causative role of Yap/Taz in these tumors in vivo.…”

“…Verteporfin was the first characterized YAP‐TEAD binding inhibitor, [ 283 ] but this compound suffers from low potency in vivo. [ 59,122,135,138,141 ] Thus, it will be of great interest to develop new and more potent inhibitors of this binding interaction, and the compound flufenamic acid is the first of a new wave of such small molecules. [ 284,285 ]…”

In vitro assays and techniques utilized in anticancer drug discovery

“…A recent study conducted by Hodgkinson, Kruger, Mokwena, and Abrahamse () used the LDH assay to evaluate cell viability of cervical cancer cells (HeLa) against photodynamic therapy. A study carried out by Dasari et al () to assess anticancer effects of verteporfin in endometrial cancer cells (HEC‐1‐A and HEC‐1‐B), the LDH assay was used as a cell viability assay. The Promega Corporation also provides sensitive fluorescence‐based cell viability assays based on two different peptide substrates (GF‐AFC and bis‐AAF‐R110) as markers to detect viable and non‐viable cells.…”

“…A study carried out by Dasari et al (2017) to assess anticancer effects of verteporfin in endometrial cancer cells (HEC-1-A and HEC-1-B), the LDH assay was used as a cell viability assay. The Promega Corporation also provides sensitive fluorescence-based cell viability assays based on two different peptide substrates (GF-AFC and bis-AAF-R110) as markers to detect viable and non-viable cells.…”