Vemurafenib Induces Senescence Features in Melanoma Cells

Haferkamp, Sebastian; Borst, Andreas; Adam, Christian; Becker, Therese M.; Motschenbacher, Stephanie; Windhövel, Simone; Hufnagel, Anita; Houben, Roland; Meierjohann, Svenja

doi:10.1038/jid.2013.6

Cited by 106 publications

(92 citation statements)

References 43 publications

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“…The effect sizes described are in the range of relevant findings described in previous publications using this methodology (14). 31 P NMR analysis revealed no significant differences in the levels of measured 31 P-containing metabolites, including NTP and PCr, between control-and vemurafenib-treated samples ( Supplementary Fig. S2).…”

Section: Resultssupporting

confidence: 70%

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The BRAF Inhibitor Vemurafenib Activates Mitochondrial Metabolism and Inhibits Hyperpolarized Pyruvate–Lactate Exchange in BRAF-Mutant Human Melanoma Cells

Delgado-Goñi

Miniotis

Wantuch

et al. 2016

Molecular Cancer Therapeutics

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Understanding the impact of BRAF signaling inhibition in human melanoma on key disease mechanisms is important for developing biomarkers of therapeutic response and combination strategies to improve long-term disease control. This work investigates the downstream metabolic consequences of BRAF inhibition with vemurafenib, the molecular and biochemical processes that underpin them, their significance for antineoplastic activity, and potential as noninvasive imaging response biomarkers.1 H NMR spectroscopy showed that vemurafenib decreases the glycolytic activity of BRAF-mutant (WM266.4 and SKMEL28) but not BRAF WT (CHL-1 and D04) human melanoma cells. In WM266.4 cells, this was associated with increased acetate, glycine, and myo-inositol levels and decreased fatty acyl signals, while the bioenergetic status was maintained.13 C NMR metabolic flux analysis of treated WM266.4 cells revealed inhibition of de novo lactate synthesis and glucose utilization, associated with increased oxidative and anaplerotic pyruvate carboxylase mitochondrial metabolism and decreased lipid synthesis. This metabolic shift was associated with depletion of hexokinase 2, acyl-CoA dehydrogenase 9, 3-phosphoglycerate dehydrogenase, and monocarboxylate transporters (MCT) 1 and 4 in BRAF-mutant but not BRAF WT cells and, interestingly, decreased BRAF-mutant cell dependency on glucose and glutamine for growth. Further, the reduction in MCT1 expression observed led to inhibition of hyperpolarized 13 C-pyruvatelactate exchange, a parameter that is translatable to in vivo imaging studies, in live WM266.4 cells. In conclusion, our data provide new insights into the molecular and metabolic consequences of BRAF inhibition in BRAF-driven human melanoma cells that may have potential for combinatorial therapeutic targeting as well as noninvasive imaging of response. Mol Cancer Ther; 15(12);

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Section: Resultssupporting

confidence: 70%

“…The bioenergetic status of treated cells, as assessed by 31 P NMR analysis of cellular NTP and PCr levels and bioluminescence-measured ATP/ADP, remained unaffected.…”

Section: Discussionmentioning

confidence: 99%

The BRAF Inhibitor Vemurafenib Activates Mitochondrial Metabolism and Inhibits Hyperpolarized Pyruvate–Lactate Exchange in BRAF-Mutant Human Melanoma Cells

Delgado-Goñi

Miniotis

Wantuch

et al. 2016

Molecular Cancer Therapeutics

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“…Cellular senescence can be triggered by overexpression or activation of oncogenes [9], and the loss of oncogene-induced senescence effectors may lead to the development of malignant tumors [7,8]. Intrinsic senescence can also be induced by therapeutic intervention, and it has been demonstrated that different antitumor drugs, such as cyclophosphamide [10] or the BRAF inhibitor vemurafenib [11], drive cancer cells into permanent growth arrest. Recently, we and others described cytokine-induced senescence (CIS) as an extrinsic form of senescence.…”

Section: Introductionmentioning

confidence: 99%

Nuclear Translocation of Argonaute 2 in Cytokine-Induced Senescence

Rentschler

Chen

Pahl

et al. 2018

Cell Physiol Biochem

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Background/Aims: Cellular senescence, or permanent growth arrest, is known as an effective tumor suppressor mechanism that can be induced by different stressors, such as oncogenes, chemotherapeutics or cytokine cocktails. Previous studies demonstrated that the growth-repressing state of oncogene-induced senescent cells depends on argonaute protein 2 (Ago2)-mediated transcriptional gene silencing and Ago2/Rb corepression of E2F-dependent cell cycle genes. Cytokine-induced senescence (CIS) likewise depends on activation of the p16^Ink4a/Rb pathway, and consecutive inactivation of the E2F family of transcription factors. In the present study, we therefore analyzed the role of Ago2 in CIS. Methods: Human cancer cell lines were treated with interferon-gamma (IFN-γ) and tumor necrosis factor (TNF) to induce senescence. Senescence was determined by growth assays and measurement of senescence-associated β-galactosidase (SA-β-gal) activity, Ago2 translocation by Ago2/ Ki67 immunofluorescence staining and western blot analysis, and gene transcription by quantitative polymerase chain reaction (qPCR). Results: IFN-γ and TNF permanently stopped cell proliferation and time-dependently increased SA-β-gal activity. After 24 – 48 h of cytokine treatment, Ago2 translocated from the cytoplasm into the nucleus of Ki67-negative cells, an effect which was shown to be reversible. Importantly, the proinflammatory cytokine cocktail suppressed Ago2-regulated cell cycle control genes, and siRNA-mediated depletion of Ago2 interfered with cytokine-induced growth inhibition. Conclusion: IFN-γ and TNF induce a stable cell cycle arrest of cancer cells that is accompanied by a fast nuclear Ago2 translocation and repression of Ago2-regulated cell cycle control genes. As Ago2 downregulation impairs cytokine-induced growth regulation, Ago2 may contribute to tissue homeostasis in human cancers.

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“…Based on this assay, treatment with a BRAF inhibitor and radiotherapy should only be considered in patients who do not exhibit an increased susceptibility for BRAF inhibitor associated radiosensitization in the tested cells of the normal tissue. [77][78][79] or initiation of apoptosis [80][81][82] and senescence [83] in BRAF V600E cancer cells mainly of melanocyte origin. Dasgupta et al [77] and Sambade et al [78] achieved a further reduction of clonogenic survival and spheroid invasion potential after X-irradiation of BRAF inhibitor treated BRAF V600E melanocytes, and both attributed to their findings to the additional G2-arrest induced by ionizing radiation.…”

Section: Radiosensitizing Effects Of Braf V600 Inhibitors In Normal Hmentioning

confidence: 99%

Radiotherapy with BRAF Inhibitor Therapy for Melanoma: Progress and Possibilities

et al. 2015

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The introduction of small molecule BRAF(V600) kinase inhibitors represents a milestone in the targeted therapy of patients with metastatic melanoma by a significant increase in therapeutic efficacy in terms of overall and progression-free survival compared with conventional chemotherapy. Beside BRAF(V600) inhibitor treatment, radiotherapy is a further mainstay for the therapy of metastatic melanoma and thus a concomitant or sequential application of BRAF(V600) inhibitors and radiotherapy is inevitable. Recent reports show a significant radiosensitization of the irradiated healthy tissue in patients with melanoma after the combination of radiotherapy and BRAF(V600) inhibitors, evoking concern in clinical practice. We review interactions of BRAF(V600) inhibitors and radiation with regard to antitumor effects and an increased radiotoxicity in the healthy tissue.

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Vemurafenib Induces Senescence Features in Melanoma Cells

Cited by 106 publications

References 43 publications

The BRAF Inhibitor Vemurafenib Activates Mitochondrial Metabolism and Inhibits Hyperpolarized Pyruvate–Lactate Exchange in BRAF-Mutant Human Melanoma Cells

The BRAF Inhibitor Vemurafenib Activates Mitochondrial Metabolism and Inhibits Hyperpolarized Pyruvate–Lactate Exchange in BRAF-Mutant Human Melanoma Cells

Nuclear Translocation of Argonaute 2 in Cytokine-Induced Senescence

Radiotherapy with BRAF Inhibitor Therapy for Melanoma: Progress and Possibilities

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