Modulation of DNA methylation levels sensitizes doxorubicin-resistant breast adenocarcinoma cells to radiation-induced apoptosis.
Chemoresistant tumors often fail to respond to other cytotoxic treatments such as radiation therapy. The mechanisms of chemo- and radiotherapy cross resistance are not fully understood and are believed to be epigenetic in nature. We hypothesize that MCF-7 cells and their doxorubicin-resistant variant MCF-7/DOX cells may exhibit different responses to ionizing radiation due to their dissimilar epigenetic status. Similar to previous studies, we found that MCF-7/DOX cells harbor much lower levels of global DNA methylation than MCF-7 cells. Furthermore, we found that MCF-7/DOX cells had lower background apoptosis levels and were less responsive to radiation than MCF-7 cells. Decreased radiation responsiveness correlated to significant global DNA hypomethylation in MCF-7/DOX cells. Here, for the first time, we show that the radiation resistance of MCF-7/DOX cells can be reversed by an epigenetic treatment--the application of methyl-donor SAM. SAM-mediated reversal of DNA methylation led to elevated radiation sensitivity in MCF-7/DOX cells. Contrarily, application of SAM on the radiation sensitive and higher methylated MCF-7 cells resulted in a decrease in their radiation responsiveness. This data suggests that a fine balance of DNA methylation is needed to insure proper radiation and drug responsiveness.
Luzhna
Lidia
L
Department of Biological Sciences, University of Lethbridge, AB T1K3M4, Canada.
Kovalchuk
Olga
O
D000230:Adenocarcinoma / Q000235:genetics* / Q000532:radiotherapy*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects*; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D006801:Humans; D011836:Radiation Tolerance / Q000187:drug effects* / Q000235:genetics; D012436:S-Adenosylmethionine / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D012436:S-Adenosylmethionine; D004317:Doxorubicin