Abstract
Uterine leiomyosarcoma (LMS) contributes to a significant proportion of uterine cancer deaths. It is a rare and high-risk gynecological cancer. LMS is challenging to the treatment due to the resistance of several therapies. The activation of the Hedgehog (HH) pathway has been reported in several types of female cancers. Uterine LMS presents an upregulation of the crucial HH signaling pathway members such as SMO and GLI1. Although targeting the HH pathway exhibited a potent inhibitory effect on the phenotype of uterine LMS in vitro, the effect of the HH inhibitors on LMS growth in vivo has not been identified. The present study aimed to assess the effect of Hedgehog pathway inhibitors (SMO-LDE225 and GLI-Gant61) as a therapeutic option in the xenograft model of uterine LMS. The results demonstrated that LDE225 treatment did not show any inhibitory effect on LMS tumor growth; however, treatment with GLI inhibitor (Gant61) induced a remarkable tumor regression with a significant decrease in Ki67 expression, compared to control (p < 0.01). Moreover, administration of Gant61 decreased the expression of GLI1, GLI target genes BMP4 and c-MYC (p < 0.05), indicating that the HH pathway is implicated in the LMS experimental model. In conclusion, our studies demonstrate for the first time that GLI inhibitor (Gant61), but not SMO inhibitor (LDE225), shows a potent inhibitory effect on LMS tumor growth and concomitantly suppresses the expression of GLI1- and GLI-targeted genes using the xenograft model of uterine LMS.
Highlights
Uterine leiomyosarcoma (LMS) contributes to a significant proportion of uterine cancer deaths [1,2,3,4]
Our in vitro study demonstrated that LDE225 (SMO) and Gant61 (GLI) inhibitors were capable of blocking the HH pathway signaling with a significant decrease in the LMS cell proliferation and migration with prominent apoptosis enhancement [26]
After the tumors developed, the animals were randomly separated into three groups (SMO inhibitor, GLI inhibitor, and control)
Summary
Uterine leiomyosarcoma (LMS) contributes to a significant proportion of uterine cancer deaths [1,2,3,4]. The deregulation of the HH signaling pathway plays an important role in more than 30% of human cancers [15] This deregulation of the HH pathway contributes to tumor initiation and progression [16,17,18,19]. Due to the important role of key HH components in cancer progression, targeting SMO and the GLIs have been demonstrated to be a useful strategy to block the HH signaling pathway activity and suppress the tumor progression [28,29,30,31,32,33]. Our in vitro study demonstrated that LDE225 (SMO) and Gant (GLI) inhibitors were capable of blocking the HH pathway signaling with a significant decrease in the LMS cell proliferation and migration with prominent apoptosis enhancement [26].
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