title: NKX3.1 contributes to S phase entry and regulates DNA damage response (DDR) in prostate cancer cell lines.
abstract: NKX3.1 is an androgen-regulated homeobox gene that encodes a tissue-restricted transcription factor, which plays an important role in the differentiation of the prostate epithelium. Thus, the role of NKX3.1 as a functional topoisomerase I activity enhancer in cell cycle regulation and the DNA damage response (DDR) was explored in prostate cancer cell lines. As an early response to DNA damage following CPT-11 treatment, we found that there was an increase in the γH2AX(S139) foci number and that total phosphorylation levels were reduced in PC-3 cells following ectopic NKX3.1 expression as well as in LNCaP cells following androgen administration. Furthermore, upon drug treatment, the increase in ATM(S1981) phosphorylation was reduced in the presence of NKX3.1 expression, whereas DNA-PKcs expression was increased. Additionally, phosphorylation of CHK2(T68) and NBS1(S343) was abrogated by ectopic NKX3.1 expression, compared with the increasing levels in control PC-3 cells in a time-course experiment. Finally, NKX3.1 expression maintained a high cyclin D1 expression level regardless of drug treatment, while total γH2AX(S139) phosphorylation remained depleted in PC-3, as well as in LNCaP, cells. Thus, we suggest that androgen regulated NKX3.1 maintains an active DDR at the intra S progression and contributes to the chemotherapeutic resistance of prostate cancer cells to DNA damaging compounds.
authors.affiliation: Ege University, Engineering Faculty, Department of Bioengineering, Cancer Biology Laboratory, Faculty of Pharmacy, Bornova, Izmir, Turkey.
authors.forename: Burcu
authors.initials: B
authors.lastname: Erbaykent-Tepedelen
authors.forename: Besra
authors.initials: B
authors.lastname: Ozmen
authors.forename: Lokman
authors.initials: L
authors.lastname: Varisli
authors.forename: Ceren
authors.initials: C
authors.lastname: Gonen-Korkmaz
authors.forename: Bilge
authors.initials: B
authors.lastname: Debelec-Butuner
authors.forename: Hamid
authors.initials: H
authors.lastname: Muhammed Syed
authors.forename: Ozgur
authors.initials: O
authors.lastname: Yilmazer-Cakmak
authors.forename: Kemal Sami
authors.initials: KS
authors.lastname: Korkmaz
mesh_terms: D000728:Androgens / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D004249:DNA Damage; D006657:Histones / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016196:S Phase; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D000728:Androgens; C468783:H2AX protein, human; D006657:Histones; D018398:Homeodomain Proteins; C491178:NKX3-1 protein, human; D014157:Transcription Factors; D000077146:Irinotecan; D002166:Camptothecin