Smoothened-independent activation of hedgehog signaling by rearranged during transfection promotes neuroblastoma cell proliferation and tumor growth

Ruan, Hongfeng; Luo, Huan; Wang, Jirong; Ji, Xing; Zhang, Zhongmiao; Wu, Junsong; Zhang, Xianning; Wu, Ximei

doi:10.1016/j.bbagen.2016.06.017

Cited by 12 publications

(4 citation statements)

References 53 publications

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“…In NB, the overexpression of Hh signaling induces maturation of cancer cells [ 10 , 11 ]. Due to its important role in tumorgenesis, anticancer drugs based on Hh ligand antagonists (e.g., 5E1 and robotnikinin), Smo inhibitors (e.g., GDC-0449 and IPI-926), and GLI transcriptional activity inhibitors (e.g., GANT-58 and GANT-61) have been developed [ 12 – 14 ].…”

Section: Introductionmentioning

confidence: 99%

The protective autophagy activated by GANT-61 in MYCN amplified neuroblastoma cells is mediated by PERK

et al. 2018

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The proto-oncogene MYC can trigger the unfolded protein response (UPR). The double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK), one of three primary branches of the UPR, is a key regulator of autophagy, promoting tumorigenesis. Upon activation of PERK, there is an increase in phosphorylation of the eukaryotic initiation factor-2 alpha (eIF2α), which in turn, activates the transcription factor-4 (ATF4), responsible for an increased expression of LC3, a common autophagy marker. PERK is repressed upon GLI1 and GLI2 induction. GANT-61 is an inhibitor of GLI1 and GLI2, known to reduce autophagy in MYCN nonamplified, but not in MYCN amplified neuroblastoma (NB) cells. In our study, we tested the effect of the joint administration of a PERK inhibitor (GSK2606414) and the GLI inhibitor GANT-61 to MYCN amplified and MYCN non-amplified NB cells. Our results suggest that inhibition of PERK impairs GANT-61 induced autophagy in NB cells with MYCN amplification, but had no effect on the MYCN non-amplified NB cells. In summary, PERK seems to be a good therapeutic target for NB. Inhibition of PERK reduces autophagy in MYCN amplified NB cells, thus amplifying the efficacy of the GLI inhibitor GANT-61 in reducing proliferation of this type of cancer cells.

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Section: Introductionmentioning

confidence: 99%

The protective autophagy activated by GANT-61 in MYCN amplified neuroblastoma cells is mediated by PERK

et al. 2018

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“…31 A number of studies have shown that the use of HH pathway antagonists cyclopamine and GANT61 to block SMO and Gli1/ 2, respectively, can significantly inhibit NB cell proliferation and increase its apoptosis; it is especially important to inhibit Gli1/2 result in down-regulating amplification of the downstream regulatory gene N-myc, which is closely related to the invasiveness and poor prognosis of high-risk NB. 32,33 The above studies suggest that it is feasible to use a targeted drug specific for Gli in the HH signaling pathway closely related to the occurrence and development of NB to treat high-risk NB and now ATO has been proven to be an inhibitor of Gli 34,35 and it may play a Large preclinical and clinical studies suggest ATO has therapeutic potential against NB.…”

Section: Discussionmentioning

confidence: 99%

Improved Outcomes with Induction Chemotherapy Combined with Arsenic Trioxide in Stage 4 Neuroblastoma: A Case Series

Feng

Chen

et al. 2021

Technol Cancer Res Treat

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Objective: The apoptotic and cytotoxic effects of arsenic trioxide (ATO) makes it a potentially suitable agent for the treatment of patients with neuroblastoma with poor prognosis; therefore, we try to evaluate the effectiveness and safety of ATO combined with reinduction/induction chemotherapy in children with recurrent/refractory or newly diagnosed stage 4 neuroblastoma. Methods: Retrospective analysis was performed on seven pediatric patients with recurrent /refractory or newly diagnosed stage 4 neuroblastoma treated with traditional reinduction/induction chemotherapy combined with ATO. Results: A total of 7 patients were treated synchronously with ATO and chemotherapy for up to nine courses; all patients received conventional chemotherapy plus a 0.16 mg/kg/day dose of intravenous ATO during reinduction/induction chemotherapy. Treatment was effective in five patients and ineffective in the other two patients. The overall response rate was 71.43% (5 of 7). The side effects of the ATO combination were minor, whereby only treatment in one patient was terminated at the sixth course due to a prolonged QT interval (0.51 s), which returned to normal after symptomatic treatment. Conclusions: ATO can be safely and effectively combined with chemotherapy drugs as a potential alternative means of treatment for high-risk stage 4 neuroblastoma, and we have observed that ATO can restore the sensitivity of chemotherapy in some patients who were resistant to previous chemotherapy. Further investigations and clinical data are required to confirm these observations.

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“…Both of these are also known to be regulated by PIK3A and TGF-β respectively. [144]. The role of GLI1 on RET expression in neuroblastoma is well documented -GLI1 induces the expression of RET [145,146].…”

Section: Discussionmentioning

confidence: 99%

A Knowledge-guided Mechanistic Model of Synthetic Lethality in the HCT116 Vorinostat-resistant Colon Cancer Xenograft Model Cell-line

Aiyetan

2021

Preprint

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With an overall lifetime risk of about 4.3% and 4.0%, in men and women respectively, colorectal cancer remains the third leading cause of cancer-related deaths in the United States. In persons aged 55 and below, its rate increased at 1% per year in the years 2008 to 2017 despite the steady decline associated with improved screening, early diagnosis and treatment in the general population. Besides standardized therapeutic regimen, many trials continue to evaluate the potential benefits of vorinostat, mostly in combination with other anti-neoplastic agents for its treatment. Vorinostat, an FDA approved anti-cancer drug known as suberoylanilide hydroxamic acid (SAHA), an histone deacylase (HDAC) inhibitor, through many mechanisms, causes cancer cell arrest and death. However, like many other anti-neoplastic agents, resistance and or failures have been observed. In the HCT116 colon cancer cell line xenograft model, exploiting potential lethal molecular interactions by additional gene knockouts restored vorinotat sensitivity. This phenomenon, known as synthetic lethality, offers a promise to selectively target cancer cells. Although without clearly delineated understanding of underlying molecular processes, it has been demonstrated as an effective cancer-killing mechanism. In this study, we aimed to elucidate mechanistic interactions in multiple perturbations of identified synthetically lethal experiments, particularly in the vorinostat-resistant HCT116 (colon cancer xenograft model) cell line. Given that previous studies showed that knocking down GLI1, a downstream transcription factor involved in the Sonic Hedgehog pathway -- an embryonal gene regulatory process, resulted in restoration of vorinostat sensitivity in the HCT116 colorectal cancer cell line, we hypothesized that vorinostat resistance is a result of upregulation of embryonal cellular differentiation processes; we hypothesized that elucidated regulatory mechanism would include crosstalks that regulate this biological process. We employed a knowledege-guided fuzzy logic regulatory inference method to elucidate mechanistic relationships. We validated inferred regulatory models in independent datasets. In addition, we evaluated the biomedical significance of key regulatory network genes in an independent clinically annotated dataset. We found no significant evidence that vorinostat resistance is due to an upregulation of embryonal gene regulatory pathways. Our observation rather support a topological rewiring of canonical oncogenic pathways around the PIK3CS, AKT, RAS/BRAF etc. regulatory pathways. Reasoning that significant regulatory network genes are likely implicated in the clinical course of colorectal cancer, we show that the identified key regulatory network genes' expression profile are able to predict short- to medium-term survival in colorectal cancer patients -- providing a rationale basis for prognostification and potentially effective combination of therapeutics that target these genes along with vorinostat in the treatment of colorectal cancer.

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Smoothened-independent activation of hedgehog signaling by rearranged during transfection promotes neuroblastoma cell proliferation and tumor growth

Cited by 12 publications

References 53 publications

The protective autophagy activated by GANT-61 in MYCN amplified neuroblastoma cells is mediated by PERK

The protective autophagy activated by GANT-61 in MYCN amplified neuroblastoma cells is mediated by PERK

Improved Outcomes with Induction Chemotherapy Combined with Arsenic Trioxide in Stage 4 Neuroblastoma: A Case Series

A Knowledge-guided Mechanistic Model of Synthetic Lethality in the HCT116 Vorinostat-resistant Colon Cancer Xenograft Model Cell-line

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