title: Para-phenylenediamine-induces apoptosis via a pathway dependent on PTK-Ras-Raf-JNK activation but independent of the PI3K/Akt pathway in NRK-52E cells.
abstract: para‑Phenylenediamine (p‑PD) is a potential carcinogen, and widely used in marketed hair dye formulations. In the present study, the role of the protein tyrosine kinase (PTK)/Ras/Raf/c‑Jun N‑terminal kinase (JNK) and phosphoinositide 3‑kinase (PI3k)/protein kinase B (Akt) pathways on the growth of NRK‑52E cells was investigated. The results demonstrated that p‑PD reduced cell viability in a dose‑dependent manner. The cell death due to apoptosis was confirmed by cell cycle analysis and an Annexin‑V‑fluorescein isothiocyanate binding assay. Subsequent to staining with 2',7'‑dichlorofluorescin diacetate, the treated cells demonstrated a significant increase in reactive oxygen species (ROS) generation compared with the controls. The effects of p‑PD on the signalling pathways were analysed by western blotting. p‑PD‑treated cells exhibited an upregulated phospho‑stress‑activated protein kinase/JNK protein expression level and downregulated Ras and Raf protein expression levels; however, Akt, Bcl‑2, Bcl‑XL and Bad protein expression levels were not significantly altered compared with the control. In conclusion, p‑PD induced apoptosis by a PTK/Ras/Raf/JNK‑dependent pathway and was independent of the PI3K/Akt pathway in NRK‑52E cells.
authors.affiliation: Department of Human Biology, Cells and Molecules, International Medical University, Kuala Lumpur 57000, Malaysia.
authors.forename: Reena A P
authors.initials: RA
authors.lastname: Kasi
authors.affiliation: Department of Human Biology, Cells and Molecules, International Medical University, Kuala Lumpur 57000, Malaysia.
authors.forename: Chye Soi
authors.initials: CS
authors.lastname: Moi
authors.affiliation: Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor 43400, Malaysia.
authors.forename: Yip Wai
authors.initials: YW
authors.lastname: Kien
authors.affiliation: Department of Human Biology, Cells and Molecules, International Medical University, Kuala Lumpur 57000, Malaysia.
authors.forename: Koh Rhun
authors.initials: KR
authors.lastname: Yian
authors.affiliation: Department of Human Biology, Cells and Molecules, International Medical University, Kuala Lumpur 57000, Malaysia.
authors.forename: Ng Wei
authors.initials: NW
authors.lastname: Chin
authors.affiliation: Jeffrey Cheah School of Medicine and Health Sciences, Monash University Sunway Campus, Bandar Sunway, Selangor 47500, Malaysia.
authors.forename: Ng Khuen
authors.initials: NK
authors.lastname: Yen
authors.affiliation: Department of Human Biology, Cells and Molecules, International Medical University, Kuala Lumpur 57000, Malaysia.
authors.forename: Gnanajothy
authors.initials: G
authors.lastname: Ponnudurai
authors.affiliation: Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor 43400, Malaysia.
authors.forename: Seow Heng
authors.initials: SH
authors.lastname: Fong
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D010655:Phenylenediamines / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051025:bcl-Associated Death Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D017304:Annexin A5; D010655:Phenylenediamines; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D048031:JNK Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); C029728:4-phenylenediamine