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

Shweta Chakradeo, Khushboo Sharma, Aisha Alhaddad, Duaa Bakhshwin, Ngoc Le, Hisashi Harada, Wataru Nakajima, William Andrew Yeudall, Suzy V. Torti, Frank M. Torti, David A. Gewirtz

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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. Whereas 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 in which p53 was knocked down using small hairpin RNA 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 enhanced 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.

Original languageEnglish (US)
Pages (from-to)803-814
Number of pages12
JournalMolecular Pharmacology
Volume87
Issue number5
DOIs
StatePublished - May 1 2015

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Autophagy
Radiation
Radiation Tolerance
Therapeutics
Non-Small Cell Lung Carcinoma
Neck
Head
Pharmacology
Cell Line
Null Lymphocytes
Gene Silencing
Head and Neck Neoplasms
Ionizing Radiation
Tumor Cell Line
Small Interfering RNA
Neoplasms
Breast
Breast Neoplasms

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

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. / Chakradeo, Shweta; Sharma, Khushboo; Alhaddad, Aisha; Bakhshwin, Duaa; Le, Ngoc; Harada, Hisashi; Nakajima, Wataru; Yeudall, William Andrew; Torti, Suzy V.; Torti, Frank M.; Gewirtz, David A.

In: Molecular Pharmacology, Vol. 87, No. 5, 01.05.2015, p. 803-814.

Research output: Contribution to journalArticle

Chakradeo, Shweta ; Sharma, Khushboo ; Alhaddad, Aisha ; Bakhshwin, Duaa ; Le, Ngoc ; Harada, Hisashi ; Nakajima, Wataru ; Yeudall, William Andrew ; Torti, Suzy V. ; Torti, Frank M. ; Gewirtz, David A. / 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. In: Molecular Pharmacology. 2015 ; Vol. 87, No. 5. pp. 803-814.
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