GLS1 promotes proliferation in hepatocellular carcinoma cells via AKT/GSK3β/CyclinD1 pathway

Xi, Jianbo; Sun, Yaocheng; Zhang, Meiting; Fa, Zhenzhong; Wan, Yan-ya; Min, Zhenyu; Xu, Hong; Xu, Chengkai; Tang, Jianjun

doi:10.1016/j.yexcr.2019.04.005

Cited by 46 publications

(33 citation statements)

References 26 publications

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“…1c). Consistent with our results, both pharmacological and genetic suppression of GLS protein caused impaired clonogenic capacity in different tumor entities 17,23,42,43 . Although reaching statistical significance, the in vitro clonogenicity was barely reduced in NSCs treated with 1 µM CB839 and moderately reduced by 10 µM C968 treatment (Fig.…”

Section: Glutaminase Inhibition Selectively Impairs the Stemness Phensupporting

confidence: 92%

A comparative pharmaco-metabolomic study of glutaminase inhibitors in glioma stem-like cells confirms biological effectiveness but reveals differences in target-specificity

et al. 2020

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Cancer cells upregulate anabolic processes to maintain high rates of cellular turnover. Limiting the supply of macromolecular precursors by targeting enzymes involved in biosynthesis is a promising strategy in cancer therapy. Several tumors excessively metabolize glutamine to generate precursors for nonessential amino acids, nucleotides, and lipids, in a process called glutaminolysis. Here we show that pharmacological inhibition of glutaminase (GLS) eradicates glioblastoma stem-like cells (GSCs), a small cell subpopulation in glioblastoma (GBM) responsible for therapy resistance and tumor recurrence. Treatment with small molecule inhibitors compound 968 and CB839 effectively diminished cell growth and in vitro clonogenicity of GSC neurosphere cultures. However, our pharmaco-metabolic studies revealed that only CB839 inhibited GLS enzymatic activity thereby limiting the influx of glutamine derivates into the TCA cycle. Nevertheless, the effects of both inhibitors were highly GLS specific, since treatment sensitivity markedly correlated with GLS protein expression. Strikingly, we found GLS overexpressed in in vitro GSC models as compared with neural stem cells (NSC). Moreover, our study demonstrates the usefulness of in vitro pharmacometabolomics to score target specificity of compounds thereby refining drug development and risk assessment.

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Section: Glutaminase Inhibition Selectively Impairs the Stemness Phensupporting

confidence: 92%

A comparative pharmaco-metabolomic study of glutaminase inhibitors in glioma stem-like cells confirms biological effectiveness but reveals differences in target-specificity

et al. 2020

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“…Thus, above combination dosage was used for the validation of further experiments. In Figure 1 G,H, various oncogenes involving proliferation (CyclinD1), anti-apoptosis (XIAP, C-FLIP, and MCL-1), DNA damage (MDC-1), and metastases (MMP-9 and VEGF-A) [ 20 , 21 , 22 , 23 ] were all effectively suppressed by regorafenib combined with magnolol. Full blot images are displayed in Figure S1 .…”

Section: Resultsmentioning

confidence: 99%

Induction of Apoptosis, Inhibition of MCL-1, and VEGF-A Expression Are Associated with the Anti-Cancer Efficacy of Magnolol Combined with Regorafenib in Hepatocellular Carcinoma

Chen

Hsu

Chen

et al. 2021

Cancers

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While regorafenib was approved for the treatment of advanced HCC in 2017, with a partial response and survival benefit; other combination agents to facilitate the efficacy of regorafenib still need to be explored. Magnolol is a potential natural anti-tumor compound for many types of cancers. Combination indexes calculated on the basis of both in vitro and in vivo models have indicated a synergistic effect of the combination of regorafenib and magnolol. The overexpression of the VEGF-A protein significantly diminished regorafenib’s inhibition of cell viability, while the transient knockdown of VEGF-A by siRNA effectively sensitized HCC cells to regorafenib. In addition, the inhibition of MCL-1 by siRNA combined with regorafenib allowed for a significantly greater inhibition of cell growth, compared to regorafenib alone. A lower protein expression level for VEGF-A and MCL-1 was found for the combination treatment of HCC in vitro and in vivo. A superior metastasis inhibition was also found in the combination group, as compared to the single-treatment groups, using a transwell assay, wound healing assay, and Western blotting. The caspase-dependent and -independent and DNA damage effects, as determined by flow cytometry and a comet assay, were increased by the combination therapy. Taken together, magnolol sensitized HCC to regorafenib, which was correlated with the reduction of VEGF-A and MCL-1 and the induction of apoptosis.

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“…It has been chronicled that Cyclin D1 overexpression is a positive modulator of cell cycle progression that induces cell overgrowth, and is an important marker of malignancy (Li X. et al, 2018). Overexpression of Cyclin D1 causes cells to pass through G1/S checkpoints, thus escalating the percentage of cells in the S phase (Xi et al, 2019). PCNA is a biosignature of cell proliferation that serves a core function in nucleic acid metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, we moreover inspected the expression of proliferation-linked proteins, entailing Cyclin D1, as well as PCNA, to validate the inhibitory effect of BJJP. CyclinD1 constitutes a modulatory protein of the cell cycle and serves an essential function in transition from G1 to S phase in a variety of tumor cells (Xi et al, 2019). PCNA is a DNA clamp essential for the replication of DNA and also participates in DNA excision repair and the control of the cell cycle (Kang et al, 2019).…”

Section: Bjjp Represses Proliferation and Induces Apoptosis Of Hcc Inmentioning

confidence: 99%

Biejiajian Pill Inhibits Carcinogenesis and Metastasis via the Akt/GSK-3β/Snail Signaling Pathway in Hepatocellular Carcinoma

Sun

Chen

Wen³

et al. 2021

Front. Pharmacol.

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Hepatocellular carcinoma (HCC) is among the most usual cancers globally. In China, Biejiajian pill (BJJP), Traditional Chinese Medicine clinical prescription, is broadly utilized for the prevention and therapy of HCC. However, the mechanisms by which BJJP exerts its effects on the prevention of tumor invasion and metastasis are still largely unknown. In this study, in vitro multiple hepatic cancer cell lines and an in vivo xenograft mice model were used to validate the preventive effects and molecular mechanisms of BJJP in HCC. We established that BJJP significantly repressed the proliferation, metastasis and infiltration of HCC cells. Furthermore, BJJP remarkably suppressed HCC cell migration, as well as invasion via epithelial-mesenchymal transition (EMT) by modulating Snail expression, which was associated with the repression of Akt/GSK-3β/Snail signaling axis activation. In vivo HCC xenograft results indicated that BJJP delayed HCC development and efficiently inhibited lung metastasis. Taken together, BJJP was shown to be an effective therapeutic agent against HCC through repression of the Akt/GSK-3β/Snail signaling cascade and EMT.

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GLS1 promotes proliferation in hepatocellular carcinoma cells via AKT/GSK3β/CyclinD1 pathway

Cited by 46 publications

References 26 publications

A comparative pharmaco-metabolomic study of glutaminase inhibitors in glioma stem-like cells confirms biological effectiveness but reveals differences in target-specificity

A comparative pharmaco-metabolomic study of glutaminase inhibitors in glioma stem-like cells confirms biological effectiveness but reveals differences in target-specificity

Induction of Apoptosis, Inhibition of MCL-1, and VEGF-A Expression Are Associated with the Anti-Cancer Efficacy of Magnolol Combined with Regorafenib in Hepatocellular Carcinoma

Biejiajian Pill Inhibits Carcinogenesis and Metastasis via the Akt/GSK-3β/Snail Signaling Pathway in Hepatocellular Carcinoma

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