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A causal link from ALK to hexokinase II overexpression and hyperactive glycolysis in EML4-ALK-positive lung cancer

Oncogene volume 35, pages 6132–6142 (2016)Cite this article

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Abstract

A high rate of aerobic glycolysis is a hallmark of malignant transformation. Accumulating evidence suggests that diverse regulatory mechanisms mediate this cancer-associated metabolic change seen in a wide spectrum of cancer. The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion protein is found in approximately 3–7% of non-small cell lung carcinomas (NSCLC). Molecular evidence and therapeutic effectiveness of FDA-approved ALK inhibitors indicated that EML4-ALK is a driving factor of lung tumorigenesis. A recent clinical study showed that NSCLC harboring EML4-ALK rearrangements displayed higher glucose metabolism compared with EML4-ALK-negative NSCLC. In the current work, we presented evidence that EML4-ALK is coupled to overexpression of hexokinase II (HK2), one of the rate-limiting enzymes of the glycolytic pathway. The link from EML4-ALK to HK2 upregulation is essential for a high rate of glycolysis and proliferation of EML4-ALK-rearranged NSCLC cells. We identified hypoxia-inducible factor 1α (HIF1α) as a key transcription factor to drive HK2 gene expression in normoxia in these cells. EML4-ALK induced hypoxia-independent but glucose-dependent accumulation of HIF1α protein via both transcriptional activation of HIF1α mRNA and the phosphatidylinositol 3 kinase-AKT pathway to enhance HIF1α protein synthesis. The EML4-ALK-mediated upregulation of HIF1α, HK2 and glycolytic metabolism was also highly active in vivo as demonstrated by fluorodeoxyglucose-positron emission tomography imaging of xenografts grown from EML4-ALK-positive NSCLC cells. Our data reveal a novel EML4-ALK-HIF1α-HK2 cascade to enhance glucose metabolism in EML4-ALK-positive NSCLC.

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Acknowledgements

The work was supported in part by Astar Biotech research award (XF), the Jeffress Memorial Fund award (XF) and the NIH grant P30 CA16059 to Massey Cancer Center of VCU School of Medicine.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA

    Y Ma, E M Mohamed, H Shao & X Fang

  2. College of Life Sciences, Wuhan University, Wuhan, Hubei, China

    C Yu

  3. Department of Radiology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA

    L Wang, G Sundaresan & J Zweit

  4. Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA

    M Idowu

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Ma, Y., Yu, C., Mohamed, E. et al. A causal link from ALK to hexokinase II overexpression and hyperactive glycolysis in EML4-ALK-positive lung cancer. Oncogene 35, 6132–6142 (2016). https://doi.org/10.1038/onc.2016.150

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