ERK and JNK signaling pathways are involved in the regulation of activator protein 1 and cell death elicited by three isothiocyanates in human prostate cancer PC-3 cells

• Published in: Carcinogenesis (New York) Vol. 27; no. 3; pp. 437 - 445
• Main Authors: Xu, Changjiang, Shen, Guoxiang, Yuan, Xiaoling, Kim, Jung-hwan, Gopalkrishnan, Avantika, Keum, Young-Sam, Nair, Sujit, Kong, Ah-Ng Tony
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.03.2006; Oxford Publishing Limited (England)
• Subjects: 12-O-tetradecanoylphorbol-13-acetate; activator protein 1; AITC; allyl isothiocyanate; Anticarcinogenic Agents - pharmacology; AP-1; Apoptosis; Biological and medical sciences; c-Jun N-terminal kinase; Carcinogenesis, carcinogens and anticarcinogens; ERK; Extracellular Signal-Regulated MAP Kinases - metabolism; extracellular signal-regulated protein kinase; Food Preservatives - pharmacology; Gynecology. Andrology. Obstetrics; Humans; isothiocyanate; Isothiocyanates - pharmacology; ITC; JNK; JNK Mitogen-Activated Protein Kinases - metabolism; Male; Male genital diseases; MAPK; Medical sciences; mitogen-activated protein kinase; Nephrology. Urinary tract diseases; PEITC; phenethyl isothiocyanate; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; SFN; Signal Transduction; sulforaphane; Thiocyanates - pharmacology; TPA; Transcription Factor AP-1 - biosynthesis; Transcription, Genetic; Transfection; Tumor Cells, Cultured; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Human; Urinary system disease; Prostate disease; Extracellular signal-regulated protein kinase; Enzyme; Mitogen-activated protein kinase; Malignant tumor; Signaling pathway; Cell death; Male genital diseases; Prostate cancer; Isothiocyanates; Tumor cell; Apoptosis; Transcription factor AP1
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgi251

Many isothiocyanates (ITCs) such as sulforaphane (SFN), phenethyl isothiocyanate (PEITC) and allyl isothiocyanate (AITC) are highly effectively in chemoprevention or reduction of the risk of cancer and possess antitumor activities in vitro and in vivo. The activator protein 1 (AP-1) and MAPK signaling pathways are believed to play an important role in cancer chemoprevention and chemotherapy due to their involvement in tumor cell growth, proliferation, apoptosis and survival. In the present study, we determined the effects of SFN, PEITC and AITC on AP-1 activation, and investigated the roles of extracellular signal-regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways in the regulation of AP-1 activation and cell death elicited by these ITCs in human prostate cancer PC-3 cells. SFN, PEITC and AITC each induced AP-1 activity potently and caused a significant elevation in the phosphorylation of ERK1/2, JNK1/2, Elk-1 and c-Jun. Transfection with ERK2 and upstream kinase DNEE-MEK1 activated AP-1 activity, and transfection with dominant-negative mutant ERK2 (dnERK2) potently decreased AP-1 activation induced by SFN, PEITC and AITC. Transfection with JNK1 and upstream kinase MKK7 activated AP-1 activity, and transfection with dominant-negative mutant JNK1-APF significantly attenuated AP-1 activation induced by SFN, PEITC and AITC. Pretreatment with MEK1-ERK inhibitor U0126 and JNK inhibitor SP600125 substantially attenuated the decrease in cell viability induced by SFN, PEITC and AITC. Transfection with dnERK2 and JNK1-APF significantly reversed the decrease of Bcl-2 expression elicited by these ITCs. Furthermore, transfection with dnERK2 and JNK1-APF blocked the apoptosis induced by these ITCs in PC-3 cells. Taken together, our results indicate that the activation of the ERK and JNK signaling pathways is important for transcriptional activity of AP-1 and is involved in the regulation of cell death elicited by ITCs in PC-3 cells.