Akt2 and acid ceramidase cooperate to induce cell invasion and resistance to apoptosis

Berndt, Norbert; Patel, Ronil A.; Yang, Hua; Balasis, Maria E.; Sebti, Saı̈d M.

doi:10.4161/cc.25043

Cited by 8 publications

(6 citation statements)

References 57 publications

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“…Previous pharmacological and gene-silencing experiments have suggested that AC participates in the control of cancer cell proliferation and malignancy 45 , 46 . In the present report, the complete suppression of AC expression was found to cause a stronger reduction in proliferation and invasion capabilities compared to previous studies 20 . As described, the cell-permeant ceramide analog C6 causes cell cycle arrest in the G1/S phase 25 .…”

Section: Discussioncontrasting

confidence: 56%

“…Second, pharmacological inhibition of AC activity sensitizes prostate cancer cells to the effects of radiation 15 and fenretinide 16 , promotes Fas-induced apoptosis in head-and-neck cancer 17 , increases daunorubicin cytotoxicity in hepatoma cells 18 and enhances cytotoxicity of several classes of chemotherapeutic drugs in colon cancer 19 and melanoma cells 5 , 8 . Finally, siRNA-guided silencing of the ASAH1 gene reduces hepatocellular carcinoma growth in vivo 18 and synergizes with silencing of Akt to enhance death in a variety of cancer cell lines in vitro 20 , 21 .…”

Section: Introductionmentioning

confidence: 99%

“…The role of AC in balancing ceramide and sphingosine/S1P levels is reasonably well established. The consequences of the long-term suppression of this balance by removal of AC are unknown, because all experiments conducted thus far have relied upon gene silencing or pharmacological approaches that do not achieve complete and prolonged AC suppression 19 , 20 , 25 . To overcome this limitation, in the present study we used CrispR/Cas9-mediated gene editing to remove the ASAH1 gene and its protein product from A375 melanoma cells, which are known for their high invasiveness and self-renewal capabilities 26 .…”

Section: Introductionmentioning

confidence: 99%

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Complete Acid Ceramidase ablation prevents cancer-initiating cell formation in melanoma cells

Lai

Realini

Ferla

et al. 2017

Sci Rep

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Acid ceramidase (AC) is a lysosomal cysteine hydrolase that catalyzes the conversion of ceramide into fatty acid and sphingosine. This reaction lowers intracellular ceramide levels and concomitantly generates sphingosine used for sphingosine-1-phosphate (S1P) production. Since increases in ceramide and consequent decreases of S1P reduce proliferation of various cancers, AC might offer a new target for anti-tumor therapy. Here we used CrispR-Cas9-mediated gene editing to delete the gene encoding for AC, ASAH1, in human A375 melanoma cells. ASAH1-null clones show significantly greater accumulation of long-chain saturated ceramides that are substrate for AC. As seen with administration of exogenous ceramide, AC ablation blocks cell cycle progression and accelerates senescence. Importantly, ASAH1-null cells also lose the ability to form cancer-initiating cells and to undergo self-renewal, which is suggestive of a key role for AC in maintaining malignancy and self-renewal of invasive melanoma cells. The results suggest that AC inhibitors might find therapeutic use as adjuvant therapy for advanced melanoma.

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Section: Discussioncontrasting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Complete Acid Ceramidase ablation prevents cancer-initiating cell formation in melanoma cells

Lai

Realini

Ferla

et al. 2017

Sci Rep

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“…The dysregulation of phosphorylation-dependent signaling pathways is a hallmark of oncogenesis ( Bhatia et al, 2010 ; Berndt et al, 2013 ; Liu et al, 2018 ). Early this century, the first tyrosine kinase inhibitor (TKI) was approved as a potential precision therapy for HCC ( da Fonseca et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Single-Cell RNA Sequencing Reveals the Role of Phosphorylation-Related Genes in Hepatocellular Carcinoma Stem Cells

Yao

et al. 2022

Front. Cell Dev. Biol.

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Abnormal activation of protein kinases and phosphatases is implicated in various tumorigenesis, including hepatocellular carcinoma (HCC). Advanced HCC patients are treated with systemic therapy, including tyrosine kinase inhibitors, which extend overall survival. Investigation of the underlying mechanism of protein kinase signaling will help to improve the efficacy of HCC therapy. Combining single-cell RNA sequencing data and TCGA RNA-seq data, we profiled the protein kinases, phosphatases, and other phosphorylation-related genes (PRGs) of HCC patients in this study. We found nine protein kinases and PRGs with high expression levels that were mainly detected in HCC cancer stem cells, including POLR2G, PPP2R1A, POLR2L, PRC1, ITBG1BP1, MARCKSL1, EZH2, DTYMK, and AURKA. Survival analysis with the TCGA dataset showed that these genes were associated with poor prognosis of HCC patients. Further correlation analysis showed that these genes were involved in cell cycle-related pathways that may contribute to the development of HCC. Among them, AURKA and EZH2 were identified as two hub genes by Ingenuity Pathway Analysis. Treatment with an AURKA inhibitor (alisertib) and an EZH2 inhibitor (gambogenic) inhibited HCC cell proliferation, migration, and invasion. We also found that both AURKA and EZH2 were highly expressed in TP53-mutant HCC samples. Our comprehensive analysis of PRGs contributes to illustrating the mechanisms underlying HCC progression and identifying potential therapeutic targets for future clinical trials.

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“…Furthermore, Akt-2 and aCDase have been shown to cooperate to induce cell invasion and confer resistance to apoptosis. Combination of Akt and aCDase inhibitors synergistically inhibit cell viability/proliferation more effectively than single-agent treatments [37]. Moreover, aCDase has been described as an estrogen-dependent enzyme that might provide prognostic information in ER-positive breast cancers [38].…”

Section: Acid Ceramidasementioning

confidence: 99%

Small Molecule Inhibitors of Ceramidases

Saied

2014

Cell Physiol Biochem

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The equilibrium between the pro-apoptotic ceramide and pro-vital sphingosine-1-phosphate is considered to be decisive for cell death or survival. The different ceramidases thus play key roles in cell fate and might offer attractive targets for pharmacological intervention. Although until recently only moderately active inhibitors have been described, first in vivo experiments suggest activity against cancer cell survival and multi-drug resistance. Here, we provide a brief overview on the different ceramidases, and we will review the known inhibitors and current strategies for further inhibitor development.

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Akt2 and acid ceramidase cooperate to induce cell invasion and resistance to apoptosis

Cited by 8 publications

References 57 publications

Complete Acid Ceramidase ablation prevents cancer-initiating cell formation in melanoma cells

Complete Acid Ceramidase ablation prevents cancer-initiating cell formation in melanoma cells

Single-Cell RNA Sequencing Reveals the Role of Phosphorylation-Related Genes in Hepatocellular Carcinoma Stem Cells

Small Molecule Inhibitors of Ceramidases

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