Verteporfin reverses progestin resistance through YAP/TAZ-PI3K-Akt pathway in endometrial carcinoma

Abstract

Progestin resistance is a problem for patients with endometrial carcinoma (EC) who require conservative treatment with progestin, and its underlying mechanisms remain unclear. YAP and TAZ (YAP/TAZ), downstream transcription coactivators of Hippo pathway, promote viability, metastasis and also drug resistance of malignant tumors. According to our microarray analysis, YAP/TAZ were upregulated in progestin resistant IshikawaPR cell versus progestin sensitive Ishikawa cell, which implied that YAP/TAZ may be a vital promotor of resistance to progestin. We found YAP/TAZ had higher expression levels among the resistant tissues than sensitive tissues. In addition, knocking down YAP/TAZ decreased cell viability, inhibited cell migration and invasion and increased the sensitivity of IshikawaPR cell to progestin. On the contrary, overexpression of YAP/TAZ increased cell proliferation, metastasis and promoted progestin resistance. We also confirmed YAP/TAZ were involved in progestin resistant process by regulating PI3K-Akt pathway. Furthermore, Verteporfin as an inhibitor of YAP/TAZ could increase sensitivity of IshikawaPR cells to progestin in vivo and in vitro. Our study for the first time indicated that YAP/TAZ play an important role in progestin resistance by regulating PI3K-Akt pathway in EC, which may provide ideas for clinical targeted therapy of progestin resistance.

MKLN1-AS promotes pancreatic cancer progression as a crucial downstream mediator of HIF-1α through miR-185-5p/TEAD1 pathway

“…An integral component of the Hippo signaling pathway, TEAD1 is known for its involvement in processes such as tumor cell proliferation, migration, epithelial-mesenchymal transition (Li et al 2022 ), and drug resistance (Wei et al 2023 ). The first report TEAD1 in PDAC promotion was acting as the transcription enhancer factor bound by MSLN element to enhance MSLN expression (Hucl et al 2007 ).…”

Exploiting Matrix Stiffness to Overcome Drug Resistance

“…290−293 Verteporfin, an FDA approved YAP/TAZ inhibitor, has been reported to suppress cancer stem cell phenotype and progrestin resistance in mesothelioma and endometrial carcinoma. 294 In addition, phase I/II clinical trial for treating EGFR-mutated glioblastoma patients with verteporfin has been initiated. 295 The matrix stiffness relationship with stemness in cancer is summarized (Figure 3c).…”

“…Both canonical and noncanonical Wnt signaling pathways play a significant role in promoting cancer stem cell phenotypes. Previous reports demonstrated the involvement of the Wnt signaling pathway in gaining stem cell characteristics and chemoresistance in colon cancer. , Furthermore, the Notch pathway plays a critical role in the self-renewal ability of cancer stem cells, the EMT, and in the chemoresistance of platinum-based chemotherapeutics. , Lastly, both the Hedgehog and JAK/STAT pathways are reported to mediate the self-renewal capacities of cancer stem cells and chemoresistance in various cancer types. − Verteporfin, an FDA approved YAP/TAZ inhibitor, has been reported to suppress cancer stem cell phenotype and progrestin resistance in mesothelioma and endometrial carcinoma . In addition, phase I/II clinical trial for treating EGFR-mutated glioblastoma patients with verteporfin has been initiated .…”

Targeting the YAP/TAZ mechanotransducers in solid tumour therapeutics

“…VP targeting of the YAP/TAZ pathway is also effective to overcome drug resistance in endometrial carcinoma (EC). YAP/TAZ mediates resistance to progestin through the phosphoinositide 3‐kinase (PI3K)/Akt pathway, and VP sensitizes EC cells to progestin both in vitro and in vivo 23 . It also demonstrates an additive antitumor effect when combined with the histone demethylase lysine‐specific demethylase 1 (LSD1) inhibitor SP2509 in vitro and in vivo in oral squamous cell carcinoma cells 24 …”