EGFR-mediated Rad51 expression potentiates intrinsic resistance in prostate cancer via EMT and DNA repair pathways

To study the role of EGFR signaling in regulation of intrinsic resistance in prostate cancer. Radioresistant prostate carcinoma DU145 and PC-3 cells were used to study the effect of shRNA-mediated knockdown of EGFR on intrinsic radioresistance mechanisms. Semi-quantitative PCR, western blotting, gro...

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Bibliographic Details
Published in:Life sciences (1973) 2021-12, Vol.286, p.120031-120031, Article 120031
Main Authors: Rajput, Mohit, Singh, Ragini, Singh, Navneendra, Singh, Rana P.
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
AKT protein
Biomarkers
Cell migration
Cell proliferation
Chromones - pharmacology
Damage
Deoxyribonucleic acid
DNA
DNA Damage
DNA damage repair
DNA Repair
DNA-dependent protein kinase
Drug Resistance, Neoplasm - drug effects
E-cadherin
EGFR
EMT
Epidermal growth factor receptors
Epithelial-Mesenchymal Transition - drug effects
ErbB Receptors - genetics
ErbB Receptors - metabolism
Erlotinib Hydrochloride - pharmacology
Gene expression
Gene regulation
Growth kinetics
Humans
Inhibitors
Male
Mesenchyme
Morpholines - pharmacology
Prostate cancer
Prostate carcinoma
Prostatic Neoplasms - pathology
Proteins
Rad51
Rad51 Recombinase - metabolism
Radioresistance
Repair
Transcription
Vimentin
Western blotting
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Summary:To study the role of EGFR signaling in regulation of intrinsic resistance in prostate cancer. Radioresistant prostate carcinoma DU145 and PC-3 cells were used to study the effect of shRNA-mediated knockdown of EGFR on intrinsic radioresistance mechanisms. Semi-quantitative PCR, western blotting, growth kinetics, colony formation, transwell migration, invasion and trypan blue assays along with inhibitors erlotinib, NU7441, B02, PD98059 and LY294002 were used. EGFR knock-down induced morphological alterations along with reduction in clonogenic potential and cell proliferation in DU145 cells. Migratory potential of prostate cancer cells were reduced concomitant with upregulation of epithelial marker, E-cadherin and decreased expression of mesenchymal markers, vimentin and snail. Further, EGFR knock-down decreased the expression of Rad51 and DNA-PK at mRNA as well as protein levels. Likewise, erlotinib, an EGFR inhibitor, and NU7441, a DNA-PK inhibitor increased the expression of E-cadherin and decreased the level of vimentin. Both these inhibitors also decreased the levels of DNA damage regulatory protein Rad51. Further, Rad51 inhibitor, B02, inhibited the clonogenic potential, cell migration and reduced the expression of vimentin, Ku70 and Ku80, and also, B02 radiosensitized DU145 cells. EGFR-regulated expression of Rad51 was found to be mediated via PI3K/Akt and Erk1/2 pathways. EGFR was found to regulate DNA damage repair, survival and EMT responses in prostate cancer cells through transcriptional regulation of Rad51. A novel role of EGFR-Erk1/2/Akt-Rad51 axis through modulation of EMT and DNA repair pathways in prostate cancer resistance mechanisms is suggested. [Display omitted] •EGFR regulates intrinsic resistance in prostate cancer (PCa) through Rad51.•EGFR-Rad51 regulates DNA damage repair, survival and EMT in PCa.•Kinase regulates mRNA and protein level of Rad51 and DNA-PK.•Rad51 inhibitor, B02, inhibited clonogenic and migration potential of resistant PCa cells.
ISSN:0024-3205
1879-0631
DOI:10.1016/j.lfs.2021.120031