Effect of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against human Merkel cell carcinoma MKL-1 cells

Lin, Zhenyu; Hong, Ming; Fan, Jiquan; Yin, Zhongyuan; Wu, Gang

doi:10.3892/ol.2015.3791

Cited by 10 publications

(9 citation statements)

References 31 publications

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“…Consistent with previous reports [ 13 , 14 ], BEZ235 treatment of AQR and H1975DM cells led to G1 cell cycle arrest (Figure 1B ) and reduced cell migration (Figure 1C ), but had no significant effect on apoptosis levels (Figure 1D ). When compared to H1975DM cells, the AQR clones had a reduced G1 block, reduced impedance of cell migration, but no difference in induced apoptosis levels following BEZ235 treatment.…”

Section: Resultssupporting

confidence: 93%

Acquired resistance to PI3K/mTOR inhibition is associated with mitochondrial DNA mutation and glycolysis

et al. 2017

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Acquired resistance (AQR) to drug treatment occurs frequently in cancer patients and remains an impediment to successful therapy. The aim of this study was to gain insight into how AQR arises following the application of PI3K/mTOR inhibitors. H1975 lung cancer cells with EGFR T790M mutations that confer resistance to EGFR inhibitors underwent prolonged treatment with the PI3K/mTOR inhibitor, BEZ235. Monoclonal cells with stable and increased resistance to BEZ235 were obtained after 8 months treatment. These AQR clones showed class-specific resistance to PI3K/mTOR inhibitors, reduced G1 cell cycle arrest and impedance of migration following PI3K/mTOR inhibition, reduced PTEN expression and increased Akt and S6RP phosphorylation. Transcriptome analysis revealed the AQR clones had increased expression of the metabolite transporters SLC16A9 and SLC16A7, suggestive of altered cell metabolism. Subsequent experiments revealed that AQR clones possess features consistent with elevated glycolysis, including increased levels of glucose, lactate, glutamine, glucose dependence, GLUT1 expression, and rates of post-glucose extracellular acidification, and decreased levels of reactive oxygen species and rates of oxygen consumption. Combination treatment of BEZ235 with the glycolysis inhibitor 3-bromopyruvate was synergistic in AQR clones, but only additive in parental cells. DNA sequencing revealed the presence of a mitochondrial DNA (mtDNA) MT-C01 variant in AQR but not parental cells. Depletion of mitochondrial DNA in parental cells induced resistance to BEZ235 and other PI3K/mTOR inhibitors, and was accompanied by increased glycolysis. The results of this study provide the first evidence that a metabolic switch associated with mtDNA mutation can be an underlying mechanism for AQR.

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Section: Resultssupporting

confidence: 93%

Acquired resistance to PI3K/mTOR inhibition is associated with mitochondrial DNA mutation and glycolysis

et al. 2017

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“…Here, we demonstrate that increased AKT phosphorylation in MCC was reduced significantly in response to myriocin and SKI-II treatment ( Figure 5). Phosphorylation of AKT at S 473 is increased in MCC cell lines in vitro and MCC tumors in situ (Hafner et al, 2012;Lin et al, 2015). Because both inhibitors decreased the extracellular S1P content (Figure 2), it is conceivable that diminished availability of S1P results in reduced basal AKT phosphorylation.…”

Section: Discussionmentioning

confidence: 98%

Pharmacological Inhibition of Serine Palmitoyl Transferase and Sphingosine Kinase-1/-2 Inhibits Merkel Cell Carcinoma Cell Proliferation

Bhat

Bernhart

Plastira

et al. 2019

Journal of Investigative Dermatology

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The majority of Merkel cell carcinoma, a highly aggressive neuroendocrine cancer of the skin, is associated with Merkel cell polyomavirus infection. Polyomavirus binding, internalization, and infection are mediated by glycosphingolipids. Besides receptor function, bioactive sphingolipids are increasingly recognized as potent regulators of several hallmarks of cancer. Merkel cell polyomavirus þ and Merkel cell polyomavirus e cells express serine palmitoyl transferase subunits and sphingosine kinase (SK) 1/2 mRNA. Induced expression of Merkel cell polyomaviruselarge tumor antigen in human lung fibroblasts resulted in upregulation of SPTLC1-3 and SK 1/2 expression. Therefore, we exploited pharmacological inhibition of sphingolipid metabolism as an option to interfere with proliferation of Merkel cell polyomavirus þ Merkel cell carcinoma cell lines. We used myriocin (a serine palmitoyl transferase antagonist) and two SK inhibitors (SKI-II and ABC294640). In MKL-1 and WaGa cells myriocin decreased cellular ceramide, sphingomyelin, and sphingosine-1-phosphate content. SKI-II increased ceramide species but decreased sphingomyelin and sphingosine-1-phosphate concentrations. Aberrant sphingolipid homeostasis was associated with reduced cell viability, increased necrosis, procaspase-3 and PARP processing, caspase-3 activity, and decreased AKT S473 phosphorylation. Myriocin and SKI-II decreased tumor size and Ki-67 staining of xenografted MKL-1 and WaGa tumors on the chorioallantoic membrane. Our data suggest that pharmacological inhibition of sphingolipid synthesis could represent a potential therapeutic approach in Merkel cell carcinoma.Myriocin induced a dose-dependent decrease of MKL-1 and WaGa cell viability. At the highest concentration used, CellTiter-Glo assay luminescence signals were reduced by VK Bhat et al.

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“…However PI3K pathway upregulation in MCC is independent of MCPyV and provides rationale for the use of PI3K inhibitors, such as ZSTK474 and NVP‐BEZ235, for both virus‐positive and ‐negative MCC . NVP‐BEZ235 inhibits proliferation and induces cell‐cycle arrest in MCC cell lines by upregulating cell‐cycle inhibitors p21 and p27 . Subunits of PI3K, such as p110δ, are detected in 71‐100% of MCC lines and have an unclear contribution to pathway activation .…”

Section: Discussionmentioning

confidence: 99%

“…86,87 NVP-BEZ235 inhibits proliferation and induces cell-cycle arrest in MCC cell lines by upregulating cell-cycle inhibitors p21 and p27. 88 Subunits of PI3K, such as p110δ, are detected in 71-100% of MCC lines and have an unclear contribution to pathway activation. 89 Idelalisib, a selective PI3K-δ inhibitor was used successfully in a patient with stage-IV MCC 90 ; however, further studies demonstrated weak effects in MCC tissues and cell lines.…”

Section: Pi3k-akt-mtor Pathwaymentioning

confidence: 99%

Molecular and immune targets for Merkel cell carcinoma therapy and prevention

Cohen

Tsai

2019

Molecular Carcinogenesis

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Merkel cell carcinoma (MCC) is a rare neuroendocrine carcinoma of the skin, for which the exact mechanisms of carcinogenesis remain unknown. Therapeutic options for this highly aggressive malignancy have historically been limited in both their initial response and response durability. Recent improvements in our understanding of MCC tumor biology have expanded therapeutic options for these patients, namely through the use of immunotherapies such as immune checkpoint inhibitors. Further elucidation of the tumor mutational landscape has identified molecular targets for therapies, which have demonstrated success in other cancer types. In this review, we discuss both current and investigational immune and molecular targets of therapy for MCC.

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Effect of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against human Merkel cell carcinoma MKL-1 cells

Cited by 10 publications

References 31 publications

Acquired resistance to PI3K/mTOR inhibition is associated with mitochondrial DNA mutation and glycolysis

Acquired resistance to PI3K/mTOR inhibition is associated with mitochondrial DNA mutation and glycolysis

Pharmacological Inhibition of Serine Palmitoyl Transferase and Sphingosine Kinase-1/-2 Inhibits Merkel Cell Carcinoma Cell Proliferation

Molecular and immune targets for Merkel cell carcinoma therapy and prevention

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