RT Journal Article
SR Electronic
T1 Yet Another Function of p53: The Switch that Determines Whether Radiation-Induced Autophagy Will be Cytoprotective or Nonprotective. Implications for Autophagy Inhibition as a Therapeutic Strategy
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.114.095273
DO 10.1124/mol.114.095273
A1 Shweta Chakradeo
A1 Khushboo Sharma
A1 Aisha Alhaddad
A1 Duaa Bakhshwin
A1 Ngoc Le
A1 Hisashi Harada
A1 Wataru Nakajima
A1 Andrew Yeudall
A1 Suzy V Torti
A1 Frank M Torti
A1 David A Gewirtz
YR 2015
UL http://molpharm.aspetjournals.org/content/early/2015/02/09/mol.114.095273.abstract
AB The influence of autophagy inhibition on radiation sensitivity was studied in human breast, head and neck and non-small cell lung cancer cell lines, in cell lines that were either wild type or mutant/null in p53 and in cells where p53 was inducible or silenced. While ionizing radiation promoted autophagy in all tumor cell lines studied, pharmacological inhibition of autophagy and/or genetic silencing of autophagy genes failed to influence sensitivity to radiation in p53 mutant Hs578t breast tumor cells, HN6 head and neck tumor cells, and H358 non-small cell lung cancer cells. The requirement for functional p53 in the promotion of cytoprotective autophagy by radiation was confirmed by the observation that radiation induced autophagy was nonprotective in p53 null H1299 cells but was converted to the cytoprotective form with induction of p53. Conversely, whereas p53 wild type HN30 head and neck cancer cells did show sensitization to radiation upon autophagy inhibition, HN30 cells where p53 was knocked down using shRNA failed to be sensitized by pharmacological autophagy inhibition. Taken together, these findings indicate that radiation-induced autophagy can be either cytoprotective or nonprotective, a functional difference related to the presence or absence of function p53. Alternatively, these findings could be interpreted to suggest that whereas radiation can induce autophagy independent of p53 status, inhibition of autophagy promotes enhances radiation sensitivity through a mechanism that requires functional p53. These observations are likely to have direct implications with respect to clinical efforts to modulate the response of malignancies to radiation through autophagy inhibition.