ABSTRACT
Radiation therapy is used to treat cancer by radiation-induced DNA damage. Despite the best efforts to eliminate cancer, some cancer cells survive irradiation, resulting in cancer progression or recurrence. Alteration in DNA damage repair pathways is common in cancers, resulting in modulation of their response to radiation. This article focuses on the recent findings about molecules and pathways that potentially can be targeted to sensitize prostate cancer cells to ionizing radiation, thereby achieving an improved therapeutic outcome.
Subject(s)
DNA Damage/radiation effects , DNA Repair/radiation effects , Prostatic Neoplasms/radiotherapy , Ataxia Telangiectasia Mutated Proteins/genetics , Ataxia Telangiectasia Mutated Proteins/radiation effects , Aurora Kinases/radiation effects , Cell Cycle/radiation effects , Checkpoint Kinase 1/radiation effects , Cyclin-Dependent Kinases/radiation effects , Cyclins/radiation effects , HSP90 Heat-Shock Proteins/radiation effects , Histone Deacetylases/radiation effects , Humans , Hyaluronan Receptors/radiation effects , Hypoxia-Inducible Factor 1, alpha Subunit/radiation effects , Male , Mutation/radiation effects , NEDD8 Protein/radiation effects , Neoplasm Recurrence, Local/etiology , Neoplasm Recurrence, Local/radiotherapy , Neoplasm, Residual , Neoplastic Stem Cells/radiation effects , Phosphatidylinositol 3-Kinases/radiation effects , Poly(ADP-ribose) Polymerases/radiation effects , Proto-Oncogene Proteins c-met/radiation effects , Radiation Tolerance , Radiation, Ionizing , Receptors, Androgen/radiation effects , TOR Serine-Threonine Kinases/radiation effects , Zinc Finger Protein GLI1/radiation effectsSubject(s)
Neoplasms/metabolism , Neural Cell Adhesion Molecule L1/adverse effects , Proto-Oncogene Proteins c-met/metabolism , Radiation Tolerance/radiation effects , Radiation-Sensitizing Agents/pharmacology , Signal Transduction/radiation effects , Tumor Necrosis Factor-alpha/metabolism , Animals , Ataxia Telangiectasia Mutated Proteins , Cell Cycle Proteins/metabolism , Cell Cycle Proteins/radiation effects , Cell Line, Tumor/radiation effects , DNA Repair/radiation effects , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/radiation effects , Fibroblasts/radiation effects , Humans , NF-kappa B/metabolism , NF-kappa B/radiation effects , Neoplasm Metastasis , Neoplasms/radiotherapy , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/radiation effects , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/radiation effects , Proto-Oncogene Proteins c-met/radiation effects , Radiation, Ionizing , Radiotherapy/adverse effects , Receptors, Growth Factor/metabolism , Signal Transduction/drug effects , Transplantation, Heterologous , Tumor Necrosis Factor-alpha/radiation effects , Tumor Suppressor Proteins/metabolism , Tumor Suppressor Proteins/radiation effectsABSTRACT
BACKGROUND: Ionizing radiation (IR) is effectively used in cancer therapy. However, in subsets of patients, a few radioresistant cancer cells survive and cause disease relapse with metastatic progression. The MET oncogene encodes the hepatocyte growth factor (HGF) receptor and is known to drive "invasive growth", a regenerative and prosurvival program unduly activated in metastasis. METHODS: Human tumor cell lines (MDA-MB-231, MDA-MB-435S, U251) were subjected to therapeutic doses of IR. MET mRNA, and protein expression and signal transduction were compared in treated and untreated cells, and the involvement of the DNA-damage sensor ataxia telangiectasia mutated (ATM) and the transcription factor nuclear factor kappa B (NF-κB) in activating MET transcription were analyzed by immunoblotting, chromatin immunoprecipitation, and use of NF-κB silencing RNA (siRNA). Cell invasiveness was measured in wound healing and transwell assays, and cell survival was measured in viability and clonogenic assays. MET was inhibited by siRNA or small-molecule kinase inhibitors (PHA665752 or JNJ-38877605). Combinations of MET-targeted therapy and radiotherapy were assessed in MDA-MB-231 and U251 xenografts (n = 5-6 mice per group). All P values were from two-sided tests. RESULTS: After irradiation, MET expression in cell lines was increased up to fivefold via activation of ATM and NF-κB. MET overexpression increased ligand-independent MET phosphorylation and signal transduction, and rendered cells more sensitive to HGF. Irradiated cells became more invasive via a MET-dependent mechanism that was further enhanced in the presence of HGF. MET silencing by siRNA or inhibition of its kinase activity by treatment with PHA665752 or JNJ-38877605 counteracted radiation-induced invasiveness, promoted apoptosis, and prevented cells from resuming proliferation after irradiation in vitro. Treatment with MET inhibitors enhanced the efficacy of IR to stop the growth of or to induce the regression of xenografts (eg, at day 13, U251 xenografts, mean volume increase relative to mean tumor volume at day 0: vehicle = 438%, 5 Gy IR = 151%, 5 Gy IR + JNJ-38877605 = 76%; difference, IR vs JNJ-38877604 + IR = 75%, 95% CI = 59% to 91%, P = .01). CONCLUSION: IR induces overexpression and activity of the MET oncogene through the ATM-NF-κB signaling pathway; MET, in turn, promotes cell invasion and protects cells from apoptosis, thus supporting radioresistance. Drugs targeting MET increase tumor cell radiosensitivity and prevent radiation-induced invasiveness.