Modulating yes-associated protein (YAP) in overcoming temozolomide chemoresistance in glioblastoma

Abstract

<p><strong><em>Objective</em></strong><strong>:</strong></p><p>The Hippo signaling pathway is often dysregulated in cancer. The study aims to investigate whether the Hippo signaling pathway contributes to temozolomide chemoresistance in glioblastoma, and to validate whether the combinational treatment of temozolomide and YAP inhibitor is effective against glioblastoma.</p><p><br></p><p><strong><em>Method:</em></strong></p><p>Temozolomide-sensitive and temozolomide-resistant U87 and U251 GBM human cell lines were previously established. Temozolomide-resistant cells were maintained in low-dose temozolomide. Here, we investigate whether Hippo signaling contributes to temozolomide chemoresistance. By modulating the Hippo signaling pathway through short-hairpin YAP gene knockdown, the outcome on GBM cancer phenotypes was studied by cell assays (in vitro) and mouse orthotopic xenograft (in vivo). Finally, the therapeutic effect of YAP inhibitor is studied in vitro and in vivo respectively.</p><p><br></p><p><strong><em>Result:</em></strong></p><p>Our data showed that YAP is overexpressed in temozolomide-resistant glioblastoma cells. Nuclear translocation of YAP (which becomes its active state) is increased in temozolomide-resistant cells. In fact, YAP inhibition demonstrates reduced cell viability and higher susceptibility to temozolomide. Mice with tumor injection of the YAP knockdown cells have significantly reduced tumor size. Similarly, YAP inhibitor resensitizes temozolomide-resistant cells to temozolomide. Mechanistically, YAP knockdown reduces cell stemness, which in turn attenuates temozolomide chemoresistance.</p><p><br></p><p><strong><em>Conclusion:</em></strong></p><p>In conclusion, our data suggests dysregulated Hippo signaling pathway contributes to temozolomide chemoresistance, thus targeting the Hippo signaling pathway resensitizes GBM cells to temozolomide. This research provides pre-clinical evidence on using YAP inhibitor for combinational therapy with temozolomide for the treatment of glioblastoma. </p>