Lactate Dehydrogenase B Is Required for the Growth of KRAS-Dependent Lung Adenocarcinomas

McCleland, Mark L.; Adler, Adam S.; Deming, Laura; Cosino, Ely; Lee, Leslie B.; Blackwood, Elizabeth M.; Solon, Margaret; Tao, Janet; Li, Li; Shames, David S.; Jackson, Erica; Forrest, William F.; Firestein, Ron

doi:10.1158/1078-0432.ccr-12-2638

Cited by 110 publications

(93 citation statements)

References 48 publications

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“…One increased transcript is hexokinase 2 (HK2), which is required for both tumor initiation and maintenance in some mouse models (53). Other transcripts consistently increased included the platelet isoform of phosphofructokinase (PFKP), which plays a critical role in driving the proliferation of breast tumors (54), lactate dehydrogenase B (LDHB), which is considered essential for triple-negative breast cancer, and KRAS-dependent lung adenocarcinomas (55).…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic characterization of fibrolamellar hepatocellular carcinoma

Simon

Freije

Farber

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

115

174

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Fibrolamellar hepatocellular carcinoma (FLHCC) tumors all carry a deletion of ∼400 kb in chromosome 19, resulting in a fusion of the genes for the heat shock protein, DNAJ (Hsp40) homolog, subfamily B, member 1, DNAJB1, and the catalytic subunit of protein kinase A, PRKACA. The resulting chimeric transcript produces a fusion protein that retains kinase activity. No other recurrent genomic alterations have been identified. Here we characterize the molecular pathogenesis of FLHCC with transcriptome sequencing (RNA sequencing). Differential expression (tumor vs. adjacent normal tissue) was detected for more than 3,500 genes (log2 fold change ≥1, false discovery rate ≤0.01), many of which were distinct from those found in hepatocellular carcinoma. Expression of several known oncogenes, such as ErbB2 and Aurora Kinase A, was increased in tumor samples. These and other dysregulated genes may serve as potential targets for therapeutic intervention.

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Section: Resultsmentioning

confidence: 99%

Transcriptomic characterization of fibrolamellar hepatocellular carcinoma

Simon

Freije

Farber

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

115

174

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“…In a number of papers, it is shown that the high level of LDH in small-cell lung cancer is an unfavorable prognostic sign associated with a low response to an administered therapy, [39] similar results have been obtained for adenocarcinoma. [40] Being an enzyme involved in anaerobic metabolism, LDH can influence a malignant potential of the tumor through various mechanisms, including increased proliferation, survival rate and invasive capacity of tumor cells, as well as reduced apoptosis. [41,42] Note that only in squamous cell lung carcinoma, there was a statistically significant decrease in the AST activity by 13.8% compared to the control group, preconditioning the most significant decrease in the de Ritis coefficient.…”

Section: Discussionmentioning

confidence: 99%

The activity of metabolic enzymes in the saliva of lung cancer patients

Bel’skaya¹,

Kosenok²

2017

Natl J Physiol Pharm Pharmacol

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Background: So far, optimization problems for diagnostics and prognostication aids have been still relevant for lung cancer as a leader in the structure of cancers. Aims and Objectives: A search for regularities of changes in the saliva enzyme activity in patients with lung cancer. Materials and Methods: In the case-control study, 859 people divided into two groups took part: Primary (lung cancer, n = 286) and control (conventionally healthy, n = 573). All the participants went through a questionnaire survey, saliva biochemical counts, and a histological verification of their diagnosis. The enzyme activity was measured by spectrophotometry. Between group differences were measured with the nonparametric test. Results: In terms of lung cancer, we observe metabolic changes described with decreased de Ritis coefficient (P ˂ 0.001), as well as the increased activity of alanine aminotransferase (P = 0.022), alkaline phosphatase (P ˂ 0.001), gamma-glutamyl transpeptidase (P = 0.043), and α-amylase (P ˂ 0.001). We have identified specifics of the change in the enzyme activity depending on a histological type and a growth form of the tumor. There is the observable increased activity of α-amylase in the saliva in lung adenocarcinoma and neuroendocrine tumors (P ˂ 0.001). It has been found that irrespective of the histological type of lung cancer in a transition from central to peripheral forms of growth; there is the observable increased activity of all the enzymes. The significantly reduced activity of aspartate aminotransferase (by 51.4% for adenocarcinoma, P = 0.032; 48.8% for squamous cell lung cancer, P = 0.042) is a distinctive feature of central lung cancer. Conclusion: The nature of the change in the enzyme activity is ambiguous and to a greater degree depends on the tumor form of growth (central/peripheral lung cancer) than the histological type (adenocarcinoma/squamous cell lung cancer).

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“…As LDH-B kinetically favours the backward reaction of pyruvatelactate conversion (Augoff et al, 2014), this may suggest that LDH-A, which mostly catalyses the formation of lactate, is more relevant to cancer than LDH-B (Maekawa, 1988). However, recent evidence has shown that higher tissue expression of LDH-B correlates to overall survival in lung cancer and treatment response in breast cancer (Dennison et al, 2013;McCleland et al, 2013), highlighting the role of LDH-B in cancer progression. Given the scarcity of data regarding the long-term impact of differential LDH expression on cancer survival, further investigations are needed to confirm the clinical usefulness of LDH with respect to its subunits or isoenzymes.…”

Section: Discussionmentioning

confidence: 99%