A small interfering RNA screen of genes involved in DNA repair identifies tumor-specific radiosensitization by POLQ knockdown

The effectiveness of radiotherapy treatment could be significantly improved if tumor cells could be rendered more sensitive to ionizing radiation (IR) without altering the sensitivity of normal tissues. However, many of the key therapeutically exploitable mechanisms that determine intrinsic tumor ra...

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Vydané v:Cancer research (Chicago, Ill.) Ročník 70; číslo 7; s. 2984
Hlavní autori: Higgins, Geoff S, Prevo, Remko, Lee, Yin-Fai, Helleday, Thomas, Muschel, Ruth J, Taylor, Steve, Yoshimura, Michio, Hickson, Ian D, Bernhard, Eric J, McKenna, W Gillies
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States 01.04.2010
Predmet:
Antineoplastic Agents, Alkylating - pharmacology
Cell Line, Tumor
Cell Survival - genetics
Cell Survival - radiation effects
Dacarbazine - analogs & derivatives
Dacarbazine - pharmacology
DNA Polymerase theta
DNA Repair - genetics
DNA-Directed DNA Polymerase - deficiency
DNA-Directed DNA Polymerase - genetics
DNA-Directed DNA Polymerase - metabolism
Gene Knockdown Techniques
HeLa Cells
Histones
Humans
Infrared Rays
Neoplasms - drug therapy
Neoplasms - genetics
Neoplasms - radiotherapy
Radiation Tolerance - genetics
RNA, Small Interfering - genetics
Temozolomide
Transfection
ISSN:1538-7445, 1538-7445
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Shrnutí:The effectiveness of radiotherapy treatment could be significantly improved if tumor cells could be rendered more sensitive to ionizing radiation (IR) without altering the sensitivity of normal tissues. However, many of the key therapeutically exploitable mechanisms that determine intrinsic tumor radiosensitivity are largely unknown. We have conducted a small interfering RNA (siRNA) screen of 200 genes involved in DNA damage repair aimed at identifying genes whose knockdown increased tumor radiosensitivity. Parallel siRNA screens were conducted in irradiated and unirradiated tumor cells (SQ20B) and irradiated normal tissue cells (MRC5). Using gammaH2AX foci at 24 hours after IR, we identified several genes, such as BRCA2, Lig IV, and XRCC5, whose knockdown is known to cause increased cell radiosensitivity, thereby validating the primary screening end point. In addition, we identified POLQ (DNA polymerase ) as a potential tumor-specific target. Subsequent investigations showed that POLQ knockdown resulted in radiosensitization of a panel of tumor cell lines from different primary sites while having little or no effect on normal tissue cell lines. These findings raise the possibility that POLQ inhibition might be used clinically to cause tumor-specific radiosensitization.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1538-7445
1538-7445
DOI:10.1158/0008-5472.CAN-09-4040