title: A causal link from ALK to hexokinase II overexpression and hyperactive glycolysis in EML4-ALK-positive lung cancer.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ma
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, Hubei, China.
authors.forename: C
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Mohamed
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Shao
authors.affiliation: Department of Radiology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Radiology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Sundaresan
authors.affiliation: Department of Radiology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zweit
authors.affiliation: Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Idowu
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Fang
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D064593:Heterografts; D006593:Hexokinase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: C522504:EML4-ALK fusion protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; D006593:Hexokinase; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose