AKT-mediated enhanced aerobic glycolysis causes acquired radioresistance by human tumor cells

Tsutomu Shimura, Naoto Noma, Yui Sano, Yasushi Ochiai, Toshiyuki Oikawa, Manabu Fukumoto, Naoki Kunugita

Research output: Contribution to journalArticlepeer-review

71 Citations (Scopus)

Abstract

Background and purpose Cellular radioresistance is a major impediment to effective radiotherapy. Here, we demonstrated that long-term exposure to fractionated radiation conferred acquired radioresistance to tumor cells due to AKT-mediated enhanced aerobic glycolysis.

Material and methods Two human tumor cell lines with acquired radioresistance were established by long-term exposure to fractionated radiation with 0.5 Gy of X-rays. Glucose uptake was inhibited using 2-deoxy-d-glucose, a non-metabolizable glucose analog. Aerobic glycolysis was assessed by measuring lactate concentrations. Cells were then used for assays of ROS generation, survival, and cell death as assessed by annexin V staining.

Results Enhanced aerobic glycolysis was shown by increased glucose transporter Glut1 expression and a high lactate production rate in acquired radioresistant cells compared with parental cells. Inhibiting the AKT pathway using the AKT inhibitor API-2 abrogated these phenomena. Moreover, we found that inhibiting glycolysis with 2-deoxy-d-glucose suppressed acquired tumor cell radioresistance.

Conclusions Long-term fractionated radiation confers acquired radioresistance to tumor cells by AKT-mediated alterations in their glucose metabolic pathway. Thus, tumor cell metabolic pathway is an attractive target to eliminate radioresistant cells and improve radiotherapy efficacy.

Original languageEnglish
Pages (from-to)302-307
Number of pages6
JournalRadiotherapy and Oncology
Volume112
Issue number2
DOIs
Publication statusPublished - 2014 Aug 1

Keywords

  • 2-Deoxy-d-glucose
  • AKT
  • Glut1
  • Glycolysis
  • Radioresistance

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Radiology Nuclear Medicine and imaging

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