Glucose-6-Phosphate Dehydrogenase Is Not Essential for K-Ras-Driven Tumor Growth or Metastasis.

TitleGlucose-6-Phosphate Dehydrogenase Is Not Essential for K-Ras-Driven Tumor Growth or Metastasis.
Publication TypeJournal Article
Year of Publication2020
AuthorsGhergurovich, JM, Esposito, M, Chen, Z, Wang, JZ, Bhatt, V, Lan, T, White, E, Kang, Y, Guo, JYanxiang, Rabinowitz, JD
JournalCancer Res
Date Published2020 Sep 15
KeywordsAnimals, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cell Proliferation, Colonic Neoplasms, Disease Models, Animal, Female, Gene Knockdown Techniques, Genes, ras, Glucosephosphate Dehydrogenase, HCT116 Cells, Humans, Lung Neoplasms, Mice, Mice, Nude, Neoplasm Transplantation, Neoplastic Cells, Circulating, Oxidative Stress, Triple Negative Breast Neoplasms

<p>The enzyme glucose-6-phosphate dehydrogenase (G6PD) is a major contributor to NADPH production and redox homeostasis and its expression is upregulated and correlated with negative patient outcomes in multiple human cancer types. Despite these associations, whether G6PD is essential for tumor initiation, growth, or metastasis remains unclear. Here, we employ modern genetic tools to evaluate the role of G6PD in lung, breast, and colon cancer driven by oncogenic K-Ras. Human HCT116 colorectal cancer cells lacking G6PD exhibited metabolic indicators of oxidative stress, but developed into subcutaneous xenografts with growth comparable with that of wild-type controls. In a genetically engineered mouse model of non-small cell lung cancer driven by K-Ras G12D and p53 deficiency, G6PD knockout did not block formation or proliferation of primary lung tumors. In MDA-MB-231-derived human triple-negative breast cancer cells implanted as orthotopic xenografts, loss of G6PD modestly decreased primary site growth without ablating spontaneous metastasis to the lung and moderately impaired the ability of breast cancer cells to colonize the lung when delivered via tail vein injection. Thus, in the studied K-Ras tumor models, G6PD was not strictly essential for tumorigenesis and at most modestly promoted disease progression. SIGNIFICANCE: K-Ras-driven tumors can grow and metastasize even in the absence of the oxidative pentose pathway, a main NADPH production route.</p>

Alternate JournalCancer Res
PubMed ID32661137
PubMed Central IDPMC7501231
Grant ListDP1 DK113643 / DK / NIDDK NIH HHS / United States
P30 CA072720 / CA / NCI NIH HHS / United States
R01 CA237347 / CA / NCI NIH HHS / United States
K22 CA190521 / CA / NCI NIH HHS / United States
R01 CA163591 / CA / NCI NIH HHS / United States
F31 CA192461 / CA / NCI NIH HHS / United States