Hedgehog Signaling in Prostate Cancer and Its  Therapeutic Implication

Gonnissen, Annelies; Isebaert, Sofie; Haustermans, Karin

doi:10.3390/ijms140713979

Cited by 89 publications

(96 citation statements)

References 148 publications

(204 reference statements)

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“…Canonical HH pathway activation appears to be more marked in late-stage prostate cancer (22,23). In addition, results of the present study and previous studies observed a potential association between HH signaling component expression and androgen-independent prostate cancer cells (1,15). Long-term androgen deprivation may induce an upregulation of HH signaling in human specimens and in cell lines.…”

Section: Discussionsupporting

confidence: 64%

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

Yang

Liu

et al. 2017

Oncol Lett

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Abstract. Ectopic activation of the canonical Hedgehog signaling pathway is involved in the development and progression of prostate cancer, which is one of the leading causes of cancer-associated mortality in males worldwide. However, the role of the non-canonical Hedgehog signaling pathway in prostate cancer remains generally unexplored. In the present study, it was identified that Gli (glioma-associated oncogene)1 and Gli2 were highly expressed at the protein level in the androgen-independent prostate cancer cell lines PC3 and DU145, but not in the androgen-dependent cancer cell line LNCaP. Silencing of Gli1 using small interfering RNA markedly decreased PC3 cell viability and liquid colony formation in vitro. The Gli1/2-specific inhibitor GANT61 markedly decreased cell viability by inducing cell apoptosis in PC3 and DU145 cells. GANT61 also alleviated liquid colony formation efficiency in PC3 and DU145 cells, suggesting that the activity of Gli1 is required for prostate cancer cell survival. To explore further the upstream signaling pathway involved in the regulation of Gli1 expression, it was identified that tumor necrosis factor α-triggered mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase 1 (S6K1) activation was required for Gli1 expression. Pharmacological and genetic inhibition of S6K1 activation markedly decreased Gli1 and its downstream target gene mRNA expression. In addition, the phosphoinositide 3-kinase/mTOR inhibitor BEZ235 markedly decreased in vitro PC3 cell proliferation. The results of the present study indicate that the non-canonical Hedgehog pathway (mTOR/S6K1/Gli1) contributes to the development and progression of prostate cancer and that Gli1 is a potential therapeutic target in the treatment of prostate cancer.

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Section: Discussionsupporting

confidence: 64%

“…Prostate cancer is the second most common malignancy in males worldwide, characterized by its high mortality and poor prognosis (1). In spite of early detection techniques and multidisciplinary therapeutic approaches, the overall 5-year survival rate remains <30% in China (2).…”

Section: Introductionmentioning

confidence: 99%

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

Yang

Liu

et al. 2017

Oncol Lett

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“…However, it plays a crucial role in regulating CSCs in various human cancers including PCa by regulating target genes involved in proliferation, survival, metastasis, and auto-regulation [37,[63][64][65] . Furthermore, the Hh pathway promotes multidrug resistance by increasing the transcription of the ABC transporter proteins ABCB1 and ABCG2 in PCa [63,64] . Thus, the inhibition of the Hh signaling pathway may result in the depletion of CSCs [37,63] .…”

Section: Hh Pathwaymentioning

confidence: 99%

Cancer Stem Cells in Prostate Cancer: Implications for Targeted Therapy

Leão¹,

Domingos

Figueiredo

et al. 2017

Urol Int

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Prostate cancer (PCa) is the most frequently diagnosed cancer in men and the second most common cause of cancer-related mortality among men in the developed world. Conventional anti-PCa therapies include surgery, radiation, hormonal ablation, and chemotherapy. Despite increasing efforts, these therapies are not effective for patients with advanced and/or metastatic disease. In most cases, cancer therapies fail due to an incomplete depletion of tumor cells, resulting in tumor relapse. The cancer stem cell (CSC) hypothesis is an emerging model that explains many of the molecular characteristics of oncological disease as well as the tendency of cancers to relapse, metastasize, and develop resistance to conventional therapies. CSCs are a reservoir of cancer cells that exhibit properties of self-renewal and the ability to reestablish the heterogeneous tumor cell population. The existence of PCa stem cells offers a theoretical explanation for many uncertainties regarding PCa and also for treatment resistance and disease progression once clinical cure is achieved. Therapies targeting CSCs might therefore lead to more effective cancer treatments, divergent from a traditional anti-proliferative approach, based on tumor bulk reduction accompanied by CSC-specific inhibition. Here, we focus on reviewing the historical perspective as well as concepts regarding stem cells and CSCs in PCa. In addition, we will report possible strategies and new clinical approaches that address the CSC-based concept of tumorigenesis in PCa.

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“…NICD and CSL form a ternary complex together with Mastermind (Mam) that recruits transcription factors activating target gene expression. Because hedgehog (Hh) signaling regulates progenitor cell fate in normal development and homeostasis, aberrant pathway activation might be involved in the maintenance of such a population in cancer [61]. Abnormal Hh signaling has been associated with diverse human malignancies including basal cell carcinoma, medulloblastoma, pancreatic and lung cancer.…”

Section: Signal For Self-renewal and Differentiation Of Stem Cellsmentioning

confidence: 99%

Stem Cells and Cancer

Ali¹

2016

J Cell Sci Ther

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Stem cells are undifferentiated cells that can differentiate into specialized cell and can divide to produce more stem cells. The concept of cancer stem cells has been discussed in the scientific literature since the 19th century. Circumstantial evidence suggests that most tumors are heterogeneous and contain a small population of cancer stem cells that exhibit distinctive self-renewal, proliferation and differentiation capabilities, which are believed to play a crucial role in tumor progression, drug resistance, recurrence and metastasis in multiple malignancies. Unlike normal adult stem cells that remain constant in number, cancer stem cells can increase in number as tumors grow, and give rise to progeny that can be both locally invasive and colonize distant sites-the two hallmarks of malignancy. Rapid advances in the cancer stem cell field have provided cause for optimism for the development of more reliable cancer therapies in the future. Strategies aimed at efficient targeting of cancer stem cells are becoming important for monitoring the progress of cancer therapy and for evaluating new therapeutic approaches.

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Hedgehog Signaling in Prostate Cancer and Its Therapeutic Implication

Cited by 89 publications

References 148 publications

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

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

Cancer Stem Cells in Prostate Cancer: Implications for Targeted Therapy

Stem Cells and Cancer

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