title: Infiltrating mast cells increase prostate cancer chemotherapy and radiotherapy resistances via modulation of p38/p53/p21 and ATM signals.
abstract: Early studies indicated that mast cells in prostate tumor microenvironment might influence prostate cancer (PCa) progression. Their impacts to PCa therapy, however, remained unclear. Here we found PCa could recruit more mast cells than normal prostate epithelial cells then alter PCa chemotherapy and radiotherapy sensitivity, leading to PCa more resistant to these therapies. Mechanism dissection revealed that infiltrated mast cells could increase p21 expression via modulation of p38/p53 signals, and interrupting p38-p53 signals via siRNAs of p53 or p21 could reverse mast cell-induced docetaxel chemotherapy resistance of PCa. Furthermore, recruited mast cells could also increase the phosphorylation of ATM at ser-1981 site, and inhibition of ATM activity could reverse mast cell-induced radiotherapy resistance. The in vivo mouse model with xenografted PCa C4-2 cells co-cultured with mast cells also confirmed that mast cells could increase PCa chemotherapy resistance via activating p38/p53/p21 signaling. Together, our results provide a new mechanism showing infiltrated mast cells could alter PCa chemotherapy and radiotherapy sensitivity via modulating the p38/p53/p21 signaling and phosphorylation of ATM. Targeting this newly identified signaling may help us better suppress PCa chemotherapy and radiotherapy resistance.
authors.affiliation: Chawnshang Chang Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Xie
authors.affiliation: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Li
authors.affiliation: Chawnshang Chang Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Dang
authors.affiliation: Chawnshang Chang Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Luke S
authors.initials: LS
authors.lastname: Chang
authors.affiliation: Chawnshang Chang Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000201:enzymology / Q000528:radiation effects*; D008819:Mice, Nude; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D034622:RNA Interference; D011836:Radiation Tolerance; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D043823:Taxoids / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C495901:TP53 protein, human; D043823:Taxoids; D016159:Tumor Suppressor Protein p53; D000077143:Docetaxel; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D048051:p38 Mitogen-Activated Protein Kinases
keywords: ATM; docetaxel; p38; prostate cancer; radiotherapy