Inhibition of Gli1‑mediated prostate cancer cell proliferation by inhibiting the mTOR/S6K1 signaling pathway

Yang, Hong; Hu, Libing; Liu, Zhimin; Qin, Yang; Li, Ruiqian; Zhang, Guoying; Zhao, Bin; Bi, Chengwei; Lei, Yonghong; Bai, Yu

doi:10.3892/ol.2017.7254

Cited by 18 publications

(17 citation statements)

References 28 publications

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“…GANT61 inhibits GLI1/2-controlled luciferase expression at high doses (IC 50 ≈ 10 µM), abolishes GLI1-regulated genes [ 206 ] and subsequent megakaryocytic differentiation [ 207 ]. GANT61 also induces apoptosis in many cancer and leukemia models such as gastric cancer [ 208 ], Ewing sarcoma [ 209 ], biliary tract cancer [ 210 ], lung cancer [ 211 ], breast cancer [ 212 , 213 ], prostate carcinoma [ 214 , 215 ] and adult T-cell leukemia or acute myeloid leukemia [ 216 , 217 ]. GANT61 induces autophagy in pancreatic ductal adenocarcinoma cells and prevents cellular migration in osteosarcoma metastasis [ 218 ] and ovarian and breast cancer invasion [ 212 , 219 ].…”

Section: Targeting Transcription Factor Through a Binding Pocketmentioning

confidence: 99%

Targeting Transcription Factors for Cancer Treatment

et al. 2018

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Transcription factors are involved in a large number of human diseases such as cancers for which they account for about 20% of all oncogenes identified so far. For long time, with the exception of ligand-inducible nuclear receptors, transcription factors were considered as “undruggable” targets. Advances knowledge of these transcription factors, in terms of structure, function (expression, degradation, interaction with co-factors and other proteins) and the dynamics of their mode of binding to DNA has changed this postulate and paved the way for new therapies targeted against transcription factors. Here, we discuss various ways to target transcription factors in cancer models: by modulating their expression or degradation, by blocking protein/protein interactions, by targeting the transcription factor itself to prevent its DNA binding either through a binding pocket or at the DNA-interacting site, some of these inhibitors being currently used or evaluated for cancer treatment. Such different targeting of transcription factors by small molecules is facilitated by modern chemistry developing a wide variety of original molecules designed to specifically abort transcription factor and by an increased knowledge of their pathological implication through the use of new technologies in order to make it possible to improve therapeutic control of transcription factor oncogenic functions.

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Section: Targeting Transcription Factor Through a Binding Pocketmentioning

confidence: 99%

Targeting Transcription Factors for Cancer Treatment

et al. 2018

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“…Melanomas critically require HH signaling [ 27 , 28 , 29 ], presumably with activated RAS-MAPK and AKT signaling cascades [ 27 ]. HH has been described to promote oncogenesis in leukemias [ 30 , 31 , 32 , 33 , 34 ], bladder cancer [ 35 ], and prostate cancer [ 36 , 37 , 38 , 39 ].…”

Section: Introductionmentioning

confidence: 99%

Widespread Expression of Hedgehog Pathway Components in a Large Panel of Human Tumor Cells and Inhibition of Tumor Growth by GANT61: Implications for Cancer Therapy

Réda

Vachtenheim

Vlčková

et al. 2018

IJMS

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The sonic Hedgehog/GLI signaling pathway (HH) is critical for maintaining tissue polarity in development and contributes to tumor stemness. Transcription factors GLI1–3 are the downstream effectors of HH and activate oncogenic targets. To explore the completeness of the expression of HH components in tumor cells, we performed a screen for all HH proteins in a wide spectrum of 56 tumor cell lines of various origin using Western blot analysis. Generally, all HH proteins were expressed. Important factors GLI1 and GLI2 were always expressed, only exceptionally one of them was lowered, suggesting the functionality of HH in all tumors tested. We determined the effect of a GLI inhibitor GANT61 on proliferation in 16 chosen cell lines. More than half of tumor cells were sensitive to GANT61 to various extents. GANT61 killed the sensitive cells through apoptosis. The inhibition of reporter activity containing 12xGLI consensus sites by GANT61 and cyclopamine roughly correlated with cell proliferation influenced by GANT61. Our results recognize the sensitivity of tumor cell types to GANT61 in cell culture and support a critical role for GLI factors in tumor progression through restraining apoptosis. The use of GANT61 in combined targeted therapy of sensitive tumors, such as melanomas, seems to be immensely helpful.

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“…In 2010, it was found that medulloblastoma resistance towards SMO inhibitors decreased as a result of combination therapy with SMO and PI3K/AKT inhibitors [ 83 ], and recently, the combination of the SMO inhibitor, NVP-LDE-225 with the PI3K/mTOR inhibitor, NPV-BEZ-235 exhibited improved efficacy towards inhibition of self-renewal and tumorigenicity of human pancreatic cancer stem cells, compared to treatment with only one of the agents, [ 84 ]. Furthermore, inhibition of PI3K/mTOR by NPV-BEZ-235 was shown to inhibit GLI1-dependent proliferation of androgen-independent prostate cancer cells [ 85 ]. Whereas the majority of prostate cancers depends on androgens (testosterone) during the initial stage, the cancer cells progressively lose the dependency on androgens during the advanced stages; thus, the cancer cells become resistant to hormonal treatments [ 86 ].…”

Section: Mechanisms Leading To Hh/mtor Crosstalkmentioning

confidence: 99%

“…Whereas the majority of prostate cancers depends on androgens (testosterone) during the initial stage, the cancer cells progressively lose the dependency on androgens during the advanced stages; thus, the cancer cells become resistant to hormonal treatments [ 86 ]. Interestingly, the authors found that the protein levels of GLI1 and GLI2 were highly increased in the androgen-independent prostate cancer cell lines PC3 and DU145 but not in the androgen-dependent cancer cell line LNCaP [ 85 ].…”

Section: Mechanisms Leading To Hh/mtor Crosstalkmentioning

confidence: 99%

Crosstalk of Hedgehog and mTORC1 Pathways

Larsen

Møller

2020

Cells

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Hedgehog (Hh) signaling and mTOR signaling, essential for embryonic development and cellular metabolism, are both coordinated by the primary cilium. Observations from cancer cells strongly indicate crosstalk between Hh and mTOR signaling. This hypothesis is supported by several studies: Evidence points to a TGFβ-mediated crosstalk; Increased PI3K/AKT/mTOR activity leads to increased Hh signaling through regulation of the GLI transcription factors; increased Hh signaling regulates mTORC1 activity positively by upregulating NKX2.2, leading to downregulation of negative mTOR regulators; GSK3 and AMPK are, as members of both signaling pathways, potentially important links between Hh and mTORC1 signaling; The kinase DYRK2 regulates Hh positively and mTORC1 signaling negatively. In contrast, both positive and negative regulation of Hh has been observed for DYRK1A and DYRK1B, which both regulate mTORC1 signaling positively. Based on crosstalk observed between cilia, Hh, and mTORC1, we suggest that the interaction between Hh and mTORC1 is more widespread than it appears from our current knowledge. Although many studies focusing on crosstalk have been carried out, contradictory observations appear and the interplay involving multiple partners is far from solved.

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Inhibition of Gli1‑mediated prostate cancer cell proliferation by inhibiting the mTOR/S6K1 signaling pathway

Cited by 18 publications

References 28 publications

Targeting Transcription Factors for Cancer Treatment

Targeting Transcription Factors for Cancer Treatment

Widespread Expression of Hedgehog Pathway Components in a Large Panel of Human Tumor Cells and Inhibition of Tumor Growth by GANT61: Implications for Cancer Therapy

Crosstalk of Hedgehog and mTORC1 Pathways

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