Radiation Biology

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SU_45_2453 - Metabolic regulation of cancer cell response to radiation therapy.

Sunday, October 21
1:15 PM - 2:45 PM
Location: Innovation Hub, Exhibit Hall 3

Metabolic regulation of cancer cell response to radiation therapy.
T. Yazal, A. Dao, S. Dong, M. Bochkur Dratver, and E. Vlashi; UCLA, Los Angeles, CA

Purpose/Objective(s): We have previously reported that metabolic heterogeneity underlies functional heterogeneity within hierarchically organized tumors, such as breast cancer and that radiation therapy can induced a phenotype conversion of surviving cancer cells. The purpose of this study was the characterization of the metabolic changes and specific metabolic enzymes that mediate phenotype conversion of the surviving breast cancer cells into resistant breast cancer-initiating cells (BCICs). We hypothesized that key metabolic enzymes play a crucial role in metabolic re-wiring of cancer cells immediately following exposure to ionizing radiation resulting in metabolic and cellular reprogramming of the surviving cells and ultimately radioresistance.

Materials/Methods: We used a fluorescent reporter for BCICs with low proteasome activity in conjunction with functional assays (i.e. mammosphere forming assays) to characterize general metabolic changes in breast cancer cells after exposure to ionizing radiation. After isolation of non-initiating breast cancer cells to different doses of ionizing radiation (IR) we performed measurements of glucose and glutamine uptake and lactate production, as well as oxygen consumption and extracellular acidification rate in a time and dose dependent manner. In addition we performed metabolic flux experiments to characterize changes in metabolite flux after exposure to IR. We also measured enzymatic activity and cellular localization of the glycolytic enzyme PKM2 (M2 isoform of pyruvate kinase) and the pentose phosphate pathway enzyme, glucose-6-phosphate dehydrogenase (G6PDH). We used known PKM2 small molecule “activators” that promote the glycolytic activity of PKM2 (promoting its tetrameric form versus the dimeric glycolytically inactive form) to better understand the role of PKM2 as a glycolytic enzyme in regulating IR-induced metabolic re-wiring.

Results: We show that IR induced acute and delayed changes in metabolic flux, increasing flux into glycolysis and pentose phosphate pathway for detoxification of reactive oxygen species. Changes in enzymatic activity of PKM2 and G6PDH appear to regulate the metabolic re-wiring as an acute response to IR-induced oxidative stress. The enzymatic activity of PKM2 is inhibited immediately after radiation exposure, followed by a translocation to the nucleus regulating gene transcription. The acute metabolic changes facilitate re-balancing the redox state of the surviving cancer cells. The use of PKM2 activators prevents such metabolic re-wiring and significantly inhibits IR-induced cellular reprogramming of breast cancer cells into BCICs.

Conclusion: Exposure to ionizing radiation induces metabolic changes in breast cancer cells in a PKM2-dependent manner. These changes lead to an acute antioxidant response and subsequent cellular reprogramming of the surviving cells into radioresistant BCICs.

Author Disclosure: T. Yazal: None. A. Dao: None. S. Dong: None. M. Bochkur Dratver: None. E. Vlashi: None.

Erina Vlashi, PhD

Disclosure:
Employment
UCLA: Employee: Employee

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