Abstract
ABSTRACTThe identification of genetic determinants that underpin tumor radioresistance can help the development of targeted radiosensitizers or aid personalization of radiotherapy treatment. Here we identify signal recognition particle 72kDa (SRP72) as a novel gene involved in radioresistance. Knockdown of SRP72 resulted in significant radiosensitization of HeLa (cervical), PSN-1 (pancreatic), and T24 (bladder), BT-549 (breast) and MCF7 (breast) tumor lines as measured by colony formation assays. SRP72 depletion also resulted in the radiosensitization of normal lung fibroblast cell lines (HFL1 and MRC-5), demonstrating that the effect is not restricted to tumor cells. Increased radiosensitivity was not due to impaired DNA damage signaling or repair as assessed by γ-H2AX foci formation. Instead SRP72 depletion was associated with elevated levels of apoptosis after irradiation, as measured by caspase 3/7 activity, PARP-cleavage and Annexin-V staining, and with an induction of the unfolded protein response. Together, our results show that SRP72 is a novel gene involved in radioresistance.
Highlights
Radiotherapy is a critical component of cancer treatment, with more than 50% of cancer patients receiving this treatment in high-income countries.[1]
The 0 Gy plating efficiencies (PE) for signal recognition particle 72kDa (SRP72) knockdown cells were lower than the non-targeting control siRNA, suggesting that depletion of SRP72 reduces cell viability in the absence of radiation
In this paper we show for the first time that a component of the signal recognition particle, SRP72, modulates radiosensitivity
Summary
Radiotherapy is a critical component of cancer treatment, with more than 50% of cancer patients receiving this treatment in high-income countries.[1] because the maximum dose that can be safely delivered to the tumor is limited by the dose tolerance of the normal surrounding tissue,[2] the amount of radiation given to the patient is often not enough to sterilize the irradiated tumor. If tumor cells could be selectively made more sensitive to radiation, this could improve the effectiveness of radiotherapy. In an effort to identify novel determinants of tumor radiosensitivity, we recently screened a ‘kinome’ siRNA library, and identified several potential targets.[3] In this paper, we describe how one of these targets, signal recognition particle 72kDa (SRP72), modulates radiosensitivity. This differential expression between tumor and normal tissues raised the possibility that disruption of SRP72 might cause tumor specific effects and be an effective therapeutic strategy
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