Abstract
BackgroundLocal tumor control by standard fractionated radiotherapy (RT) remains poor because of tumor resistance to radiation (radioresistance). It has been suggested that cancer stem cells (CSCs) are more radioresistant than non-CSCs. In previous studies, we have shown IL-6 promotes self-renewal of CD133+ CSC-like cells. In this study, we investigated whether IL-6 plays roles not only in promoting self-renewal of CD133+ cells after radiation, but also in conferring radioresistance of CD133+ cells in NSCLC.Materials and methodsTo compare radiation sensitivity of CSCs and non-CSCs, CD133+ CSC-like and CD133- cell populations were isolated from two NSCLC cell lines, A549 and H157, by immunomagnetic separation and their sensitivities to ionizing radiation were investigated using the clonogenic survival assay. To further study the IL-6 effect on the radiosensitivity of CD133+ CSC-like cells, CD133+ cells were isolated from A549IL-6si/sc and H157IL-6si/sc cells whose intracellular IL-6 levels were manipulated via the lentiviral transduction with IL-6siRNA. Post-irradiation DNA damage was analyzed by γ-H2AX staining and Comet assay. Molecular mechanisms by which IL-6 regulates the molecules associated with DNA repair and anti-apoptosis after radiation were analyzed by Western blot and immunofluoresecence (IF) staining analyses.ResultsNSCLC CD133+ CSC-like cells were enriched upon radiation. Survival of NSCLC CD133+ cells after radiation was higher than that of CD133- cells. Survival of IL-6 expressing NSC LC CD133+ cells (sc) was higher than that of IL-6 knocked-down cells (IL-6si) after radiation. IL-6 played a role in protecting NSCLC CD133+ cells from radiation-induced DNA damage and apoptosis.ConclusionsIL-6 signaling promotes DNA repair while protecting CD133+ CSC-like cells from apoptotic death after radiation for lung cancer. A combined therapy of radiation and agents that inhibit IL-6 signaling (or its downstream signaling) is suggested to reduce CSC-mediated radioresistance in lung cancer.
Highlights
Local tumor control by standard fractionated radiotherapy (RT) remains poor because of tumor resistance to radiation
CD133+, Cancer stem cell (CSC)-like cells were enriched in A549 and H157 cell cultures upon exposure to radiation To investigate whether the population of CSCs in Non-small cell lung cancer (NSCLC) was altered after radiation, unseparated A549 and H157 parental cells were irradiated with 6 Gy gamma rays and the percentage of CD133+ cells, before and after radiation, was analyzed by flow cytometry
Consistent with the CD133+ population data (Fig. 1a) and the published result by others [9], we observed a higher number of spheres in the sphere formation assay (Fig. 1b) and expression of CSC markers in NSCLC cell lines following irradiation in IF staining (Fig. 1c)
Summary
Local tumor control by standard fractionated radiotherapy (RT) remains poor because of tumor resistance to radiation (radioresistance). Local tumor control by standard fractionated RT remains poor primarily due to tumor resistance to radiation. Accumulating evidence indicates that cancer stem cells (CSCs) exist as a very minor population in NSCLC tumors [3,4,5,6]. It has been suggested by several investigators that CSCs are more radioresistant than non-CSCs. Hittelman et al [7] and Zhang et al [8] showed that
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