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Inhibiting neddylation modification alters mitochondrial morphology and reprograms energy metabolism in cancer cells.

ABSTRACT: Abnormal activation of neddylation modification and dysregulated energy metabolism are frequently seen in many types of cancer cells. Whether and how neddylation modification affects cellular metabolism remains largely unknown. Here, we showed that MLN4924, a small-molecule inhibitor of neddylation modification, induces mitochondrial fission-to-fusion conversion in breast cancer cells via inhibiting ubiquitylation and degradation of fusion-promoting protein mitofusin 1 (MFN1) by SCF?-TrCP E3 ligase and blocking the mitochondrial translocation of fusion-inhibiting protein DRP1. Importantly, MLN4924-induced mitochondrial fusion is independent of cell cycle progression, but confers cellular survival. Mass-spectrometry-based metabolic profiling and mitochondrial functional assays reveal that MLN4924 inhibits the TCA cycle but promotes mitochondrial OXPHOS. MLN4924 also increases glycolysis by activating PKM2 via promoting its tetramerization. Biologically, MLN4924 coupled with the OXPHOS inhibitor metformin, or the glycolysis inhibitor shikonin, significantly inhibits cancer cell growth both in vitro and in vivo. Together, our study links neddylation modification and energy metabolism, and provides sound strategies for effective combined cancer therapies.

SUBMITTER: Zhou Q

PROVIDER: S-EPMC6478410 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Inhibiting neddylation modification alters mitochondrial morphology and reprograms energy metabolism in cancer cells.

Zhou Qiyin Q Li Hua H Li Yuanyuan Y Tan Mingjia M Fan Shaohua S Cao Cong C Meng Feilong F Zhu Ling L Zhao Lili L Guan Min-Xin MX Jin Hongchuan H Sun Yi Y

JCI insight 20190221 4

Abnormal activation of neddylation modification and dysregulated energy metabolism are frequently seen in many types of cancer cells. Whether and how neddylation modification affects cellular metabolism remains largely unknown. Here, we showed that MLN4924, a small-molecule inhibitor of neddylation modification, induces mitochondrial fission-to-fusion conversion in breast cancer cells via inhibiting ubiquitylation and degradation of fusion-promoting protein mitofusin 1 (MFN1) by SCFβ-TrCP E3 lig ...[more]

PMID: 30668548

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Project description:In 2020, lung cancer remains the most diagnosed entity among men and third most among women, causing approximately 1.8 million deaths worldwide with an estimated 31.5% of new cases in men and 14.6% in women, respectively (1). Moreover, metastasized non-small cell lung cancer (NSCLC) continues to be one of the cancer entities with the worst prognosis as well as disease-free and overall survival despite the recent introduction of immunotherapy, with the patients’ 5-year-survival rate ranging still only between 10-20% (1). The development of cancer and metastasis is considered a multi-step process in which many factors are the topic of ongoing investigation. Thus, the identification of novel markers and targets, which are involved in disease progression, is an essential step in improving the survival of lung cancer patients. Previously, we identified HECT and RLD domain containing E3 ubiquitin protein ligase 5 (HERC5) gene as the main target gene on 4q (6). Loss of 4q has been associated with advanced disease stage and worse prognosis in several cancer entities including lung, colorectal, pancreatic, and hepatocellular cancer (2–5). We showed that in NSCLC, HERC5 downregulation via promoter hypermethylation leads to an increase in disseminated tumor cells (DTCs) and occurrence of brain metastases in NSCLC as well as poorer overall survival (OS) (6). In hepatocellular cancer, low mRNA expression levels of HERC5 could similarly be correlated with shorter OS, which led to immune evasion by indirectly increasing infiltration by regulatory T-cells (5). It was thus postulated that HERC5 might serve as a novel metastasis suppressor gene. Originally described in the context of innate immune responses, HERC5 is known to serve as the cellular main E3 ligase of ubiquitin-like modifier interferon-stimulated gene 15 (ISG15) (7,8), thereby catalyzing the transfer of ISG15 onto target proteins – a process called ISGylation. ISGylation is not only an important primary defense mechanism against viruses and other pathogens (9,10), but also associated with various diseases such as immunodeficiencies, neurodegenerative disorders and different types of cancer (11–14). Lately, energy metabolism has been proven to have a strong influence on tumorigenesis and metastasization (15–17). Given the enhanced energy demand of highly proliferating cells, tumor cells can undergo a change in energy consumption mechanisms – such as the well-described Warburg-effect, leading to a switch between ATP production through glycolysis rather than oxidative phosphorylation (OXPHOS) (18). Despite the lower yield in ATP through glycolysis, malignant cells often prefer this pathway even in the presence of oxygen, leading to an increase in metabolic byproducts which are necessary for the elevated demand of metabolites required due to their high proliferation rates (15,16). Deregulation of ISG15 have been linked to dysfunctional mitochondria as well as altered OXPHOS activity (19–22). In this study, we aimed at further elucidating the potential metastasis suppressing role of HERC5 in NSCLC. We therefore assessed the malignant potential of HERC5 loss in in vitro and in vivo NSCLC models and could confirm its capacity to transform NSCLC cells both in vitro and in vivo into a more aggressive phenotype. We furthermore performed mass spectrometry analyses to identify the main pathways altered by differential HERC5 expression in modified NSCLC cell lines and could show that HERC5 has an influence on mitochondrial composition, and energy metabolism pathways such as OXPHOS, leading to better adaptation and survival under prolonged inhibition of oxidative phosphorylation.

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Inhibiting neddylation modification alters mitochondrial morphology and reprograms energy metabolism in cancer cells.

Publications

Inhibiting neddylation modification alters mitochondrial morphology and reprograms energy metabolism in cancer cells.

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