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Pivotal role of NAMPT in the switch of melanoma cells toward an invasive and drug-resistant phenotype.

ABSTRACT: In BRAF^V600E melanoma cells, a global metabolomic analysis discloses a decrease in nicotinamide adenine dinucleotide (NAD⁺) levels upon PLX4032 treatment that is conveyed by a STAT5 inhibition and a transcriptional regulation of the nicotinamide phosphoribosyltransferase (NAMPT) gene. NAMPT inhibition decreases melanoma cell proliferation both in vitro and in vivo, while forced NAMPT expression renders melanoma cells resistant to PLX4032. NAMPT expression induces transcriptomic and epigenetic reshufflings that steer melanoma cells toward an invasive phenotype associated with resistance to targeted therapies and immunotherapies. Therefore, NAMPT, the key enzyme in the NAD⁺ salvage pathway, appears as a rational target in targeted therapy-resistant melanoma cells and a key player in phenotypic plasticity of melanoma cells.

SUBMITTER: Ohanna M

PROVIDER: S-EPMC5900716 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Pivotal role of NAMPT in the switch of melanoma cells toward an invasive and drug-resistant phenotype.

Ohanna Mickaël M Cerezo Mickaël M Nottet Nicolas N Bille Karine K Didier Robin R Beranger Guillaume G Mograbi Baharia B Rocchi Stéphane S Yvan-Charvet Laurent L Ballotti Robert R Bertolotto Corine C

Genes & development 20180322 5-6

In BRAF<sup>V600E</sup> melanoma cells, a global metabolomic analysis discloses a decrease in nicotinamide adenine dinucleotide (NAD<sup>+</sup>) levels upon PLX4032 treatment that is conveyed by a STAT5 inhibition and a transcriptional regulation of the nicotinamide phosphoribosyltransferase (NAMPT) gene. NAMPT inhibition decreases melanoma cell proliferation both in vitro and in vivo, while forced NAMPT expression renders melanoma cells resistant to PLX4032. NAMPT expression induces transcript ...[more]

PMID: 29567766

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Project description:Observations from cultured cells, animal models and patients raise the possibility that the dependency of tumours on the therapeutic drugs to which they have acquired resistance represents a vulnerability with potential applications in cancer treatment. However, for this drug addiction trait to become of clinical interest, we must first define the mechanism that underlies it. We performed an unbiased CRISPR-Cas9 knockout screen on melanoma cells that were both resistant and addicted to inhibition of the serine/threonine-protein kinase BRAF, in order to functionally mine their genome for 'addiction genes'. Here we describe a signalling pathway comprising ERK2 kinase and JUNB and FRA1 transcription factors, disruption of which allowed addicted tumour cells to survive on treatment discontinuation. This occurred in both cultured cells and mice and was irrespective of the acquired drug resistance mechanism. In melanoma and lung cancer cells, death induced by drug withdrawal was preceded by a specific ERK2-dependent phenotype switch, alongside transcriptional reprogramming reminiscent of the epithelial-mesenchymal transition. In melanoma cells, this reprogramming caused the shutdown of microphthalmia-associated transcription factor (MITF), a lineage survival oncoprotein; restoring this protein reversed phenotype switching and prevented the lethality associated with drug addiction. In patients with melanoma that had progressed during treatment with a BRAF inhibitor, treatment cessation was followed by increased expression of the receptor tyrosine kinase AXL, which is associated with the phenotype switch. Drug discontinuation synergized with the melanoma chemotherapeutic agent dacarbazine by further suppressing MITF and its prosurvival target, B-cell lymphoma 2 (BCL-2), and by inducing DNA damage in cancer cells. Our results uncover a pathway that underpins drug addiction in cancer cells, which may help to guide the use of alternating therapeutic strategies for enhanced clinical responses in drug-resistant cancers.

Dataset Information

Pivotal role of NAMPT in the switch of melanoma cells toward an invasive and drug-resistant phenotype.

Publications

Pivotal role of NAMPT in the switch of melanoma cells toward an invasive and drug-resistant phenotype.

Similar Datasets

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