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

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.