Malignant transformation by oncogenic K‐ras requires IDH2‐mediated reductive carboxylation to promote glutamine utilization

Abstract

Dear Editor, Oncogenic K-ras mutation plays a major role in malignant transformation and induces significant alterations in cancer cell metabolism [1][2][3][4]. However, the major molecular players mediating metabolic alterations during K-ras-driven cancer development remain elusive. The observations that tumorigenesis often requires multiple hits suggest that K-ras mutation likely needs the coordination of other molecular events that enable adaptive cellular metabolism for a full malignant transformation. Based on our previous study on the impact of K-ras on mitochondrial metabolism [1,5] and our recent findings that mitochondrial isocitrate dehydrogenase 2 (IDH2) could promote the "reverse" flow of the tricarboxylic acid (TCA) cycle from α-KG to isocitrate and enhance the survival and proliferation of acute myeloid leukemia cells [6], we investigated the potential role of IDH2 in metabolic adaptation during K-ras-driven tumorigenesis.We first used a tetracycline-inducible K-ras G12V expression cell system (HEK293 T-Rex/K-ras cells) [1] to test the short-term and long-term K-ras induction effects on cell proliferation, tumor formation, and the associated changes in cellular metabolism. Acute induction of Kras G12V expression (K-ras/On) for relatively short periods (3 days to 2 weeks) resulted in a decrease in cell proliferation, whereas long-term induction of K-ras G12V expression

SQLE-mediated squalene metabolism is critical for mitochondrial biogenesis and tumor development in K-ras-driven cancer

“…To date, both historic data and research show that cancerous metabolism is not as clear-cut as previously thought. Periods of special energetic needs result in further unique metabolic phenotypes, such as during embryonic development or malignant transformation [21,22]. Given that tumors require an extensive metabolic adaptation to grow and spread, we further investigated potential effect of SQLE knockdown on mitochondrial biogenesis and function in K-ras-driven cancer cells.…”

Cancer Metabolism: Fasting Reset, the Keto-Paradox and Drugs for Undoing

“…One can reinforce these effects by decreasing the synthesis of cholesterides, using statins that are difficult to handle, or Bergamotin [ 55 ]. An interesting report [ 56 ] shows that tumors can use the glutamine entry in the citric acid cycle to form citrate and feed the lipid synthesis pathway. The role of isocitrate dehydrogenase (IDH2) is essential in this process; IDH2 mediates a reductive carboxylation to facilitate the utilization of glutamine through alpha ketoglutarate to citrate reversible steps of the Krebs cycle and feed the citrate supply to lipid synthesis.…”

Unraveling the Cancer Metabolism: Fasting Reset, Ketogenic Diet? and Therapeutic Strategies

“…This effect can be amplified by utilizing statins or Bergamotin [55] to reduce cholesterol production. An intriguing report suggests that tumors can utilize glutamine to generate citrate and synthesize fat [56], a process governed by a protein named IDH2. Long-term activation of the oncogene K-ras can escalate IDH2 activity, encouraging fat production in tumors.…”