GANT‐61 and GDC‐0449 induce apoptosis of prostate cancer stem cells through a GLI‐dependent mechanism

Abstract

Aberrant reactivation of the Sonic Hedgehog (SHH) signaling pathway promotes prostate cancer (PC) growth and progression by regulating cancer-related genes through its downstream effectors GLI1 and GLI2. Therefore, targeting the SHH-GLI pathway provides an alternative approach to avoid cancer progression. The aim of this study was to delineate the underlying molecular mechanisms by which GDC-0449 (a SMO receptor inhibitor) and GANT-61 (a GLI transcription factor inhibitor) regulate cellular proliferation and self-renewal in human PC stem cells (ProCSCs). Inhibition of the SHH signaling pathway by GANT-61 induced apoptosis with more efficacy than by GDC-0449 in ProCSCs and PC cell lines. GLI1 and GLI2 expression, promoter-binding activity and GLI-responsive luciferase reporter activity were all decreased with either GDC-0449 or GANT-61 treatment. Expression of Fas, DR4, DR5, and cleavage of caspase-3 and PARP were increased, whereas levels of PDGFR-α and Bcl-2 were reduced. Double knockout of GLI1 and GLI2 using shRNA abolished the effects observed with either GDC-0449 or GANT-61 treatment. Collectively, our results showed that GANT-61 and GDC-0449 induced ProCSC apoptosis by directly or indirectly inhibiting the activities of the GLI family transcription factors, may enhance the efficacy of PC treatment.

Triacetyl resveratrol upregulates miRNA‑200 and suppresses the Shh pathway in pancreatic cancer: A potential therapeutic agent

“…In adulthood, the Hh signaling pathway is usually repressed; however, its activity is maintained in certain stem cell populations to promote tissue renewal and regeneration. Several studies have implicated the aberrant activation of Hh signaling pathway in various human malignancies, such as medulloblastoma, rhabdomyosarcoma, hepatocellular carcinoma, pancreatic cancer, digestive tract cancer, colon cancer, breast cancer, small-cell lung carcinoma, basal cell carcinoma and prostate cancer (29)(30)(31)(32)(33)(34)(35)(36)(37)(38). Furthermore, the transcriptional activation of Gli1/2 enhances cell proliferation and cell cycle progression, whereas the inhibition of Gli1/2 attenuates cell proliferation and induces apoptosis (32,39,40).…”

Targeting Hedgehog pathway and DNA methyltransferases suppress the phenotype of uterine leiomyosarcoma cells

“…In pancreatic cancer, Gant61 induces apoptosis with downregulation of GLI expression (44). In prostate cancer, Gant61 induced apoptosis (45). In melanoma cells, LDE225 increased the percentage of apoptotic cells, inhibited cell proliferation and reduced the expression of HH pathway components (46).…”

Inibidores da via de sinalização do Sonic hedgehog: avaliação de seus efeitos in vitro em leiomioma e leiomiossarcoma uterinos

“…Em nosso estudo, a utilização de Gant61 como tratamento nas células de LMS resultou em diferenças nas expressões das proteínas GLI1, GLI2 e GLI3, além da diminuição da proliferação celular. Tong e colaboradores 2018 mostraram que células de câncer de próstata expressam, de modo basal, SMO, PTCH1, GLI1, GLI2 e SHH, mas que o tratamento com o inibidor de GLI (Gant61) também diminuiu a expressão dos componentes da via do SHH, antes hiperexpressos, além de ter induzido a diminuição da proliferação, de maneira dose-dependente (Tong et al, 2018). O uso de Gant61 também foi avaliado em linhagens celulares de câncer de mama (Benvenuto et al, 2016).…”

“…Esse efeito já foi relatado em câncer pancreático, no qual o tratamento com Gant61 além de induzir apoptose, reduziu as expressões gênica e proteica de GLI1 (Ghanbari et al, 2019). Em câncer de próstata, esse tratamento induziu apoptose já nas primeiras 24 horas, mas o efeito mais potente ocorreu quando realizado durante 72 horas (Tong et al, 2018). Já a aplicação de LDE225 para o tratamento de células de melanoma, além de aumentar a porcentagem de células apoptóticas, inibiu a proliferação celular e a expressão dos componentes da via do SHH (O'Reilly et al, 2013).…”

“…Próstata e sangue (Tong et al, 2018;Kakiuchi et al, 2017) Angiogênese (Habib and O'Shaughnessy, 2016). Em contraste, GLI1 e GLI2 são considerados efetores oncogênicos da via (Stecca and Ruiz, 2010).…”