Abstract
Alterations in KEAP1/ NF-E2 p45-related factor 2 (NFE2L2/Nrf2) signaling pathway have been reported in 23% lung adenocarcinoma patients, suggesting that deregulation of the pathway is a major cancer driver. Here we report that mitogen-activated protein (MAP) kinase phosphatase 1 (MKP-1) drives tumor growth and drug resistance by up regulating transcription factor Nrf2. In non-small cell lung cancer (NSCLC) cells and xenografts, MKP-1 knockdown triggered the down-regulation of the metabolic enzymes and cytoprotective proteins, which are the target genes of Nrf2. Consequently, the cell growth was markedly inhibited with decrease of tumor metabolisms and GSH contents. Moreover, MKP-1 silencing sensitized NSCLC cells to cisplatin treatment. Mechanistically, MKP-1 inhibited the ubiquitylation of Nrf2 via a direct interaction with the transcription factor. Nrf2 was hence stabilized and its transcriptional program was activated. Notably, Nrf2 elevated MKP-1 expression at transcriptional level. In human lung adenoma tumor samples, high levels of expression of MKP-1, Nrf2, and its target gene heme oxygenase 1 were closely correlated. Thus, MKP-1 and Nrf2 form a forward feedback loop in lung cancer cells, which stabilizing and activating Nrf2 to promote anabolic metabolism and GSH biosynthesis. This study uncovers a novel role of MKP-1 in the malignant evolution of cancers.
Highlights
Lung cancer is one of the most common cancers worldwide and ranked the first leading cause of cancer death worldwide [1]
Given that tumor cells often develop an altered metabolism to cope with the demands of increasing cell-mass during growth, we investigated whether the MKP-1-dependent proliferation involves metabolic reprogramming
Knockdown of MKP-1 decreased the activity of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP), shunting the carbon flow from glucose to ribose-5-phosphate, generating the reducing agent NADPH that is essential for maintaining cellular redox status
Summary
Lung cancer is one of the most common cancers worldwide and ranked the first leading cause of cancer death worldwide [1]. In the past ten years, big progress has been achieved in the treatment of LUAD with targeted lung cancer therapy such as drugs targeting the epidermal growth factor receptor (EGFR) mutation or the anaplastic lymphoma kinase (ALK)rearranged NSCLC patients group [3]. Mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1), known as dual specificity protein phosphatase 1 (DUSP1), is a nuclear mitogen and stress-inducible MKP that is highly expressed in different types of human tumors, including those of the lung, breast, bone, ovary, bladder, prostate, and osteosarcoma [5,6,7,8]. The phosphorylation of MAPKs on threonine and tyrosine residues by specific upstream MAPK kinases (MEKs or MKKs) leads to their activation. MKPs dephosphorylate MAPKs on tyrosine and threonine residues of the signature T-X-Y motif located within the activation loop of the kinase [9,10,11]. Whether the overexpression is a cause of, or contributes to, the malignant phenotype rather than being a consequence of cell transformation is not clear yet
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