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Interruption of nuclear factor kappaB signaling by the androgen receptor facilitates 12-O-tetradecanoylphorbolacetate-induced apoptosis in androgen-sensitive prostate cancer LNCaP cells.
Cancer Res. 2003 Nov 01; 63(21):7106-12.CR

Abstract

12-O-tetradecanoylphorbolacetate (TPA) influences proliferation, differentiation, and apoptosis in a variety of cells including prostate cancer cells. Here, we show that androgen treatment potentiates TPA-induced apoptosis in androgen-sensitive prostate cancer LNCaP cells but not in androgen-independent prostate cancer cell lines DU145 and PC-3. The use of the antiandrogen bicalutamide (Casodex) rescued LNCaP cells from 5-alpha-dihydrotestosterone (DHT)/TPA-induced apoptosis, suggesting that DHT/TPA-induced apoptosis is mediated by androgen/androgen receptor (AR). In addition, a caspase-3 inhibitor (Ac-DEVD-CHO) reduced the level of apoptosis, suggesting that DHT/TPA-mediated apoptosis occurs through a caspase-3-dependent pathway. A functional reporter assay using nuclear factor (NF) kappaB-luciferase and an electromobility gel shift assay showed that DHT suppressed NFkappaB activity. In addition, apoptosis mediated by combined DHT/TPA treatment was abrogated by overexpression of the NFkappaB subunit p65 in LNCaP-p65 cells, suggesting that NFkappaB may play an important role in regulating the effects of androgen/AR and TPA on apoptosis. Furthermore, use of the c-Jun N-terminal kinase (JNK) inhibitor SB202190 showed that the combination of DHT/TPA increased JNK activation in LNCaP cells but not in LNCaP-p65 cells, demonstrating that NFkappaB may be able to suppress JNK activity. These results indicate that androgen/AR facilitates TPA-induced apoptosis by interruption of the NFkappaB signaling pathway, leading to activation of JNK in LNCaP cells. These data describe a signaling pathway that could potentially be useful in proposed therapeutic treatment strategies exploiting combinations of different agents that control apoptosis in prostate tumors.

Authors+Show Affiliations

George Whipple Laboratory for Cancer Research, Department of Pathology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

14612503

Citation

Altuwaijri, Saleh, et al. "Interruption of Nuclear Factor kappaB Signaling By the Androgen Receptor Facilitates 12-O-tetradecanoylphorbolacetate-induced Apoptosis in Androgen-sensitive Prostate Cancer LNCaP Cells." Cancer Research, vol. 63, no. 21, 2003, pp. 7106-12.
Altuwaijri S, Lin HK, Chuang KH, et al. Interruption of nuclear factor kappaB signaling by the androgen receptor facilitates 12-O-tetradecanoylphorbolacetate-induced apoptosis in androgen-sensitive prostate cancer LNCaP cells. Cancer Res. 2003;63(21):7106-12.
Altuwaijri, S., Lin, H. K., Chuang, K. H., Lin, W. J., Yeh, S., Hanchett, L. A., Rahman, M. M., Kang, H. Y., Tsai, M. Y., Zhang, Y., Yang, L., & Chang, C. (2003). Interruption of nuclear factor kappaB signaling by the androgen receptor facilitates 12-O-tetradecanoylphorbolacetate-induced apoptosis in androgen-sensitive prostate cancer LNCaP cells. Cancer Research, 63(21), 7106-12.
Altuwaijri S, et al. Interruption of Nuclear Factor kappaB Signaling By the Androgen Receptor Facilitates 12-O-tetradecanoylphorbolacetate-induced Apoptosis in Androgen-sensitive Prostate Cancer LNCaP Cells. Cancer Res. 2003 Nov 1;63(21):7106-12. PubMed PMID: 14612503.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Interruption of nuclear factor kappaB signaling by the androgen receptor facilitates 12-O-tetradecanoylphorbolacetate-induced apoptosis in androgen-sensitive prostate cancer LNCaP cells. AU - Altuwaijri,Saleh, AU - Lin,Hui-Kuan, AU - Chuang,Kuang-Hsiang, AU - Lin,Wen-Jye, AU - Yeh,Shuyuan, AU - Hanchett,LeRoy A, AU - Rahman,Mujib M, AU - Kang,Hong-Yo, AU - Tsai,Meng-Ying, AU - Zhang,Yanqing, AU - Yang,Lin, AU - Chang,Chawnshang, PY - 2003/11/13/pubmed PY - 2004/1/17/medline PY - 2003/11/13/entrez SP - 7106 EP - 12 JF - Cancer research JO - Cancer Res VL - 63 IS - 21 N2 - 12-O-tetradecanoylphorbolacetate (TPA) influences proliferation, differentiation, and apoptosis in a variety of cells including prostate cancer cells. Here, we show that androgen treatment potentiates TPA-induced apoptosis in androgen-sensitive prostate cancer LNCaP cells but not in androgen-independent prostate cancer cell lines DU145 and PC-3. The use of the antiandrogen bicalutamide (Casodex) rescued LNCaP cells from 5-alpha-dihydrotestosterone (DHT)/TPA-induced apoptosis, suggesting that DHT/TPA-induced apoptosis is mediated by androgen/androgen receptor (AR). In addition, a caspase-3 inhibitor (Ac-DEVD-CHO) reduced the level of apoptosis, suggesting that DHT/TPA-mediated apoptosis occurs through a caspase-3-dependent pathway. A functional reporter assay using nuclear factor (NF) kappaB-luciferase and an electromobility gel shift assay showed that DHT suppressed NFkappaB activity. In addition, apoptosis mediated by combined DHT/TPA treatment was abrogated by overexpression of the NFkappaB subunit p65 in LNCaP-p65 cells, suggesting that NFkappaB may play an important role in regulating the effects of androgen/AR and TPA on apoptosis. Furthermore, use of the c-Jun N-terminal kinase (JNK) inhibitor SB202190 showed that the combination of DHT/TPA increased JNK activation in LNCaP cells but not in LNCaP-p65 cells, demonstrating that NFkappaB may be able to suppress JNK activity. These results indicate that androgen/AR facilitates TPA-induced apoptosis by interruption of the NFkappaB signaling pathway, leading to activation of JNK in LNCaP cells. These data describe a signaling pathway that could potentially be useful in proposed therapeutic treatment strategies exploiting combinations of different agents that control apoptosis in prostate tumors. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/14612503/Interruption_of_nuclear_factor_kappaB_signaling_by_the_androgen_receptor_facilitates_12_O_tetradecanoylphorbolacetate_induced_apoptosis_in_androgen_sensitive_prostate_cancer_LNCaP_cells_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=14612503 DB - PRIME DP - Unbound Medicine ER -