Pharmacological inhibition of AKT sensitizes MCF-7 human breast cancer-initiating cells to radiation

• Published in: Cellular oncology (Dordrecht) Vol. 34; no. 5; pp. 451 - 456
• Main Authors: Zhan, Jun-Fang, Wu, Liang-Ping, Chen, Long-Hua, Yuan, Ya-Wei, Xie, Guo-Zhu, Sun, Ai-Min, Liu, Ying, Chen, Zhi-Xian
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.10.2011
• Subjects: Apoptosis - drug effects; Apoptosis - radiation effects; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - radiation effects; Drug Screening Assays, Antitumor; Humans; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - enzymology; Neoplastic Stem Cells - pathology; Neoplastic Stem Cells - radiation effects; Oncology; Original Paper; Pathology; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Radiation Tolerance - drug effects; Radiation Tolerance - radiation effects; Spheroids, Cellular - drug effects; Spheroids, Cellular - enzymology; Spheroids, Cellular - pathology; Spheroids, Cellular - radiation effects; X-Rays; Radioresistance; Breast cancer; AKT; Cancer stem cells; Cancer-initiating cells
• ISSN: 2211-3428; 2211-3436; 2211-3436
• DOI: 10.1007/s13402-011-0020-1

Background Caner-initiating cells (CICs or cancer stem cells) have been shown both experimentally and clinically to be resistant to radiation. The mechanism underlying radioresistance remains unclear. Methods In the present study, we screened 51 genes which are potentially important in mediating radioresistance of breast CICs. Results The expression of AKT1 and AKT2 at protein and mRNA levels was dramatically increased among the screened genes by 8 Gy radiation treatment in MCF-7 mammosphere cells (predominantly CD24 –/low /CD44 + CICs), but not in the bulk population of MCF-7 cells (predominantly CD24 + /CD44 + ). Using apoptosis and clonogenic survival assays, we found pharmacological inhibition of AKT with selective inhibitors of AKT sensitized MCF-7 mammosphere cells, but not MCF-7 monolayer cells to radiation. Conclusion The present findings suggest that treatment with AKT inhibitors prior to ionizing radiation treatment may be a potential benefit to patients with breast cancer, in particular to eradiate breast CICs.