Cucurbitacin B induces autophagy and apoptosis by suppressing CIP2A/PP2A/mTORC1 signaling axis in human cisplatin resistant gastric cancer cells

Li, Xuewen; Duan, Chao; Ji, Juanli; Zhang, Te; Yuan, Xianglin; Zhang, Yunfei; Ma, Wenjing; Yang, Jingyuan; Yang, Liying; Jiang, Zhiguo; Yu, Huiliang; Liu, Ying

doi:10.3892/or.2017.5648

Cited by 42 publications

(25 citation statements)

References 41 publications

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“…The anticancer properties of CuB have drawn the attention of many researchers in recent years. We previously reported that CuB might target CIP2A and markedly reverse adriamycin and cisplatin resistance in breast and gastric cancer . In the present study, we report for the first time that CuB exhibits moderate anti‐GBM activity in vitro and in vivo, and enhances the efficacy of DDP, but does not show toxicity toward nude mice, demonstrating its therapeutic potential.…”

Section: Discussionsupporting

confidence: 59%

Cucurbitacin B induces inhibitory effects via CIP2A/PP2A/Akt pathway in glioblastoma multiforme

Qin

et al. 2018

Molecular Carcinogenesis

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Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a human oncoprotein that is overexpressed in multiple types of tumors and promotes the proliferation and transformation of cancer cells. However, whether CIP2A can be a new drug target for human glioblastoma multiforme (GBM) is largely unclear. In the present study, we demonstrated that the overexpression of CIP2A promotes invasive behavior in GBM, and a natural compound, cucurbitacin B (CuB), shows an anti-proliferative and anti-invasion effect in GBM cell lines. CuB effectively induces apoptosis, downregulates CIP2A expression and its downstream signaling molecule, phospho-Akt, and upregulates protein phosphatase 2A (PP2A) activity. Overexpression of CIP2A reduced CuB-inhibited growth and invasion in GBM cells. Silencing CIP2A enhanced CuB-induced invasion inhibition and apoptosis in GBM. CuB combined with cisplatin synergistically inhibited GBM cells. CuB also inhibited tumor growth in murine models. Western blot results further revealed that CuB downregulates CIP2A, and phospho-Akt in vivo. In summary, inhibition of CIP2A determines the effects of CuB-induced invasive behavior inhibition and apoptosis in GBM cells. These characteristics render CuB as a promising candidate drug for further development and for designing new effective CIP2A inhibitors.

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Section: Discussionsupporting

confidence: 59%

Cucurbitacin B induces inhibitory effects via CIP2A/PP2A/Akt pathway in glioblastoma multiforme

Qin

et al. 2018

Molecular Carcinogenesis

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“…The results implied that NUSAP1 expression was positively associated with the mTORC1 signalling pathway in GC specimens (Figure A). Previous studies reported mTORC1 signalling pathway was involved in modulating cell cycle, apoptosis, growth, EMT, migration, and invasion in various cancers . To verify the GSEA results, western blot was used to evaluate mTORC1 related effectors (mTOR, P70S6K, and S6).…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies reported mTORC1 signalling pathway had influences on cell cycle progression and apoptosis. For instance, Liu et al revealed that cucurbitacin B could induce cell apoptosis via inhibiting CIP2A/PP2A/mTORC1 signalling axis in GC. The study of Wang et al indicated that metformin contributed to G0/G1 phase cell cycle arrest through targeting the AMPK/mTOR pathway.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of NUSAP1 suppresses cell proliferation, migration, and invasion via inhibiting mTORC1 signalling pathway in gastric cancer

Lin

et al. 2019

Cell Biochemistry & Function

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Gastric cancer (GC) is one of the most common causes of cancer-related death worldwide, and outstanding biomarkers for therapeutic targets or predicting GC survival are still lacking. Increasing evidence indicated that nucleolar and spindle associated protein 1 (NUSAP1) involved in regulating the progression of various cancers; however, its specific role in GC remained unclear. In this study, we found that NUSAP1 was upregulated in the GC tissues and cell lines via analysing data from The Cancer Genome Atlas (TCGA), gene expression omnibus (GEO), qRT-PCR, and western blot assays. Patients with high NUSAP1 expression levels showed shorter freeprogression survival (FPS), larger tumour size, and higher lymphatic metastasis rate compared with those with low NUSAP1 expression. Further functional experiments revealed knockdown of NUSAP1 could inhibit the growth, migration, and invasion of GC cells in vitro and vivo. Additionally, silencing NUSAP1 induced G0/G1 phase arrest, apoptosis, and suppressed the epithelial-mesenchymal transition (EMT) process. Finally, we performed gene set enrichment analysis (GSEA) and observed NUSAP1 was positive with mTORC1 signalling pathway, which was verified by the subsequent immunoblotting. In conclusion, our findings suggested that NUSAP1 contributed to GC progression and may act as a potential therapeutic target for GC.Significance of the study: Our results firstly illuminated that NUSAP1 expression was significantly upregulated in GC tissues and predicted poor FPS. Silencing it could attenuate GC progression via inhibiting mTORC1 signalling pathway. Hence, NUSAP1 may act as a promising therapy target for GC.

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“…Topical application of CuB resulted in significant reduction of epidermal hyperplasia and inflammatory cytokines, and ameliorated psoriatic symptoms (Li et al, 2015). Natural cucurbitacins and their derivatives have been recognized as promising antitumor compounds for several types of cancer, including Non-small cell lung cancer (Marostica et al, 2017), Osteosarcoma (Zhang et al, 2017) and gastric cancer (Liu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Change in Bitterness, Accumulation of Cucurbitacin B and Expression Patterns of CuB Biosynthesis-related Genes in Melon During Fruit Development

Dai

Liu

et al. 2019

Hort. J.

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Bitterness, caused by cucurbitacins, is present in some melon fruit. Although bitter compound biosynthesis and regulation in Cucurbitaceae plants have been reported, the dynamic changes in bitterness during fruit development are unknown. Bitterness severity was measured for 19 inbred melon lines, including 14 lines of Cucumis melo var. chinensis, two var. inodorus and three var. conomon, using a panel tasting method. The data showed that bitterness severity was different in several lines of var. chinensis during fruit growth and maturation. Nb46 and Nb320, two elite parental lines of var. chinensis used in melon breeding, were used as experimental materials. Bitterness was severe at stage I, but moderate and disappeared at stage II and III in the fruit of Nb46. There was non-bitterness in the fruit of Nb320 throughout the development period. Furthermore, the cucurbitacin B (CuB) content gradually decreased in Nb46, while in Nb320, the CuB content changed little and remained at a quite low level during fruit development. Different expression patterns of the genes involved in CuB biosynthesis and regulation were found between Nb46 and Nb320. The expression levels of these genes were significantly higher in Nb46 than Nb320 in the early developmental stages, and this correlated with a higher concentration of CuB in Nb46 than Nb320. These results demonstrate that bitterness severity is different in var. chinensis during fruit developmental stages, and that the CuB biosynthesis-related genes are a critical factor in this process. We hope these findings will contribute to the breeding of non-bitter melon cultivars.

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Cucurbitacin B induces autophagy and apoptosis by suppressing CIP2A/PP2A/mTORC1 signaling axis in human cisplatin resistant gastric cancer cells

Cited by 42 publications

References 41 publications

Cucurbitacin B induces inhibitory effects via CIP2A/PP2A/Akt pathway in glioblastoma multiforme

Cucurbitacin B induces inhibitory effects via CIP2A/PP2A/Akt pathway in glioblastoma multiforme

Downregulation of NUSAP1 suppresses cell proliferation, migration, and invasion via inhibiting mTORC1 signalling pathway in gastric cancer

Change in Bitterness, Accumulation of Cucurbitacin B and Expression Patterns of CuB Biosynthesis-related Genes in Melon During Fruit Development

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