C6 ceramide dramatically increases vincristine sensitivity both<i>in vivo</i>and<i>in vitro</i>, involving AMP-activated protein kinase–p53 signaling

Chen, Min-Bin; Jiang, Qin; Liu, Yuan-yuan; Zhang, Yan; He, Bangshun; Wei, Mu-Xin; Lu, Jianwei; Ji, Yong; Lu, Peihua

doi:10.1093/carcin/bgv094

Cited by 52 publications

(94 citation statements)

References 46 publications

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“…Moreover, AMPK-mediated inhibition on the Warburg effect affects oxidative phosphorylation [21]. Besides, a number of anti-cancer drugs were shown to activate AMPK-dependent cell death pathways [22-27]. Thus, AMPK activation represents a fine strategy to inhibit cancer cells [12-14].…”

Section: Introductionmentioning

confidence: 99%

Knockdown of MAGEA6 Activates AMP-Activated Protein Kinase (AMPK) Signaling to Inhibit Human Renal Cell Carcinoma Cells

Xie

Huang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Melanoma antigen A6 (MAGEA6) is a cancer-specific ubiquitin ligase of AMP-activated protein kinase (AMPK). The current study tested MAGEA6 expression and potential function in renal cell carcinoma (RCC). Methods: MAGEA6 and AMPK expression in human RCC tissues and RCC cells were tested by Western blotting assay and qRT-PCR assay. shRNA method was applied to knockdown MAGEA6 in human RCC cells. Cell survival and proliferation were tested by MTT assay and BrdU ELISA assay, respectively. Cell apoptosis was tested by the TUNEL assay and single strand DNA ELISA assay. The 786-O xenograft in nude mouse model was established to test RCC cell growth in vivo. Results: MAGEA6 is specifically expressed in RCC tissues as well as in the established (786-O and A498) and primary human RCC cells. MAGEA6 expression is correlated with AMPKα1 downregulation in RCC tissues and cells. It is not detected in normal renal tissues nor in the HK-2 renal epithelial cells. MAGEA6 knockdown by targeted-shRNA induced AMPK stabilization and activation, which led to mTOR complex 1 (mTORC1) in-activation and RCC cell death/apoptosis. AMPK inhibition, by AMPKα1 shRNA or the dominant negative AMPKα1 (T172A), almost reversed MAGEA6 knockdown-induced RCC cell apoptosis. Conversely, expression of the constitutive-active AMPKα1 (T172D) mimicked the actions by MAGEA6 shRNA. In vivo, MAGEA6 shRNA-bearing 786-O tumors grew significantly slower in nude mice than the control tumors. AMPKα1 stabilization and activation as well as mTORC1 in-activation were detected in MAGEA6 shRNA tumor tissues. Conclusion: MAGEA6 knockdown inhibits human RCC cells via activating AMPK signaling.

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Section: Introductionmentioning

confidence: 99%

Knockdown of MAGEA6 Activates AMP-Activated Protein Kinase (AMPK) Signaling to Inhibit Human Renal Cell Carcinoma Cells

Xie

Huang

et al. 2018

Cell Physiol Biochem

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“…The cell suspension was filtered through a 50-μm cell strainer. Primary human hepatocytes were purified by triple centrifugation in ice-cold Williams' medium E (5 min, 50×g) and seeded onto collagen-coated culture plates, in complete medium, supplemented with L-glutamine (5 mM), glucose (0.06 %), HEPES (23 mM, pH 7.4), gentamycin (50 μg/mL), penicillin (50 IU/mL), streptomycin (50 μg/mL), inosine (37 μM), dimethyl sulfoxide (DMSO, 1.5 %), hydrocortisone (4.8 μg/mL), and insulin (1 μg/mL) [21,27]. Medium was changed 3 and 16 h after seeding and afterward every 24-48 h (without addition of serum).…”

Section: Isolation and Culture Of Primary Human Hepatocytesmentioning

confidence: 99%

“…After 2-3 weeks, when the tumor volumes reached 200 mm 3 , the mice were randomly divided into four groups (9-11 mice per group): saline plus liposomal ghost (Bvehicle^), AZD-8055 (20 mg/ kg, oral administration, every 2 days, for 20 days), liposomal C6 (15 mg C6 ceramide/5 mL saline/kg, intravenous injection (i.v. ), every 2 days, for 20 days [21]), or AZD-8055 plus liposomal C6 combo treatment. The mice were monitored for activity and physical condition every day, and the determination of body weight and measurement of tumor mass were performed every 4 days.…”

Section: Hepatoma Xenograft Modelsmentioning

confidence: 99%

“…The regular free C6 ceramide was not soluble when given in vivo; we then synthesized a liposome-packed C6 ceramide following the protocol of previous studies [21,32]. This liposomal C6 was first tested in cultured HepG2 cells.…”

Section: C6 Ceramide Sensitizes Azd-8055-induced Anti-tumor Activity mentioning

confidence: 99%

“…Literatures have demonstrated that short-chain ceramides (C2, C6, C8) could exert potent anti-cancer activities, either alone or in combination with other conventional chemotherapeutic agents [17][18][19][20][21][22][23][24]. For example, C6 ceramide was shown to dramatically sensitize the anti-tumor activity by doxorubicin, paclitaxel (Taxol), histone deacetylase inhibitor (HDACi), vincristine, and other chemo drugs [21][22][23][24][25][26]. Our results here show that C6 ceramide could also potentiate AZD-8055-induced anti-HCC activity.…”

Section: Introductionmentioning

confidence: 99%

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C6 ceramide sensitizes the anti-hepatocellular carcinoma (HCC) activity by AZD-8055, a novel mTORC1/2 dual inhibitor

Liu

Guo

et al. 2016

Tumor Biol.

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Aberrant activation of mammalian target of rapamycin (mTOR) plays pivotal roles in promoting hepatocellular carcinoma (HCC) tumorigenesis and chemoresistance. Here, we tested the potential anti-HCC activity by a novel mTOR complex 1/2 (mTORC1/2) dual inhibitor AZD-8055 and, more importantly, the potential AZD-8055 sensitization effect by a cell-permeable short-chain ceramide (C6). We showed that AZD-8055 mainly exerted moderate cytotoxic effect against a panel of HCC cell lines (HepG2, Hep3B, and SMMC-7721). Co-treatment of C6 ceramide remarkably augmented AZD-8055-induced HCC cytotoxicity. Meanwhile, C6 ceramide dramatically potentiated AZD-8055-induced HCC cell apoptotic death. Further studies demonstrated that AZD-8055 and C6 ceramide synergistically induced anti-survival and pro-apoptotic activity in primary cultured human HCC cells, but not in the non-cancerous human hepatocytes. Signaling studies showed that AZD-8055 and C6 ceramide synergistically suppressed Akt-mTOR complex 1/2 cascade activation. In vivo, AZD-8055 oral administration suppressed HepG2 hepatoma xenograft growth in nude mice, while moderately improving mice survival. Its anti-tumor activity was dramatically potentiated with co-administration of a liposome-packed C6 ceramide. Together, these results demonstrate that concurrent targeting mTORC1/2 by AZD-8055 exerts anti-tumor ability in preclinical HCC models, and its activity is further sensitized with co-administration of C6 ceramide.

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Periplocin inhibits the growth of pancreatic cancer by inducing apoptosis via AMPK‐mTOR signaling

Xie

Sun

et al. 2020

Cancer Medicine

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Background Periplocin is a monomeric compound that exhibits anti‐tumor activities. It is extracted from Cortex Periplocae. Objective This study aimed at determining the effect of periplocin treatment on the apoptosis and proliferation of human pancreatic cancer cells, and to elucidate on its mechanisms of action. Methods PANC1 and cfpac1 cells were treated with periplocin. Cell proliferation was detected by RTCA, Ki67 immunofluorescence, and a clonogenic assay. The transwell assay was used to examine cell migration and invasion functions. The expression of apoptosis‐associated proteins was detected by flow cytometry and western blotting. Total RNA was extracted from the treated and untreated group of PANC1 cells for RNA‐seq detection and analysis. Differentially expressed genes were screened for GO biological process and KEGG pathway analysis. Finally, CFPAC1 cells were subcutaneously inoculated into BALB / c nude mice to assess tumor growth. Results Periplocin inhibited the proliferation of PANC1 and CFPAC1 cells and induced their apoptosis by activating the AMPK/mTOR pathway and inhibiting p70 S6K. It also attenuated the cell migration, invasion, and inhibited the growth of cfpac1 xenografts in nude mice. Conclusions Periplocin inhibits human pancreatic cancer cell proliferation and induces their apoptosis by activating the AMPK / mTOR pathway.

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C6 ceramide dramatically increases vincristine sensitivity bothin vivoandin vitro, involving AMP-activated protein kinase–p53 signaling

Cited by 52 publications

References 46 publications

Knockdown of MAGEA6 Activates AMP-Activated Protein Kinase (AMPK) Signaling to Inhibit Human Renal Cell Carcinoma Cells

Knockdown of MAGEA6 Activates AMP-Activated Protein Kinase (AMPK) Signaling to Inhibit Human Renal Cell Carcinoma Cells

C6 ceramide sensitizes the anti-hepatocellular carcinoma (HCC) activity by AZD-8055, a novel mTORC1/2 dual inhibitor

Periplocin inhibits the growth of pancreatic cancer by inducing apoptosis via AMPK‐mTOR signaling

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