Downregulation of phosphodiesterase 4B (PDE4B) activates protein kinase A and contributes to the progression of prostate cancer†
Eiji Kashiwagi
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorMasaki Shiota
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorCorresponding Author
Akira Yokomizo
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.Search for more papers by this authorMomoe Itsumi
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorJunichi Inokuchi
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorTakeshi Uchiumi
Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorSeiji Naito
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorEiji Kashiwagi
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorMasaki Shiota
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorCorresponding Author
Akira Yokomizo
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.Search for more papers by this authorMomoe Itsumi
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorJunichi Inokuchi
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorTakeshi Uchiumi
Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorSeiji Naito
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorNo potential conflicts of interest were disclosed.
Abstract
BACKGROUND
Prostate cancer is the most commonly diagnosed non-cutaneous cancer in American men. Unfortunately, few successful therapies for castration-resistant prostate cancer (CRPC) exist. The protein kinase A (PKA) pathway is a critical mediator of cellular proliferation and differentiation in various normal and cancerous cells. However, the PKA activity and the mechanism of regulation in CRPC remain unclear. Then, in this study, we intended to reveal the PKA activity and the mechanism of regulation in CRPC.
METHODS
Western blotting, quantitative real-time polymerase chain reaction, cytotoxicity analysis, and cell proliferation assay were used to resolve the regulatory role of PKA in prostate cancer cell line, LNCaP and their derivatives.
RESULTS
cAMP-specific phosphodiesterase 4B (PDE4B) was downregulated and the PKA pathway was activated in castration-resistant LNCaP derivatives (CxR cells). Rolipram activated the PKA pathway via inhibition of PDE4B, resulting in AR transactivation while the PKA inhibitor, H89 reduced AR transactivation. In response to hydrogen peroxide and in hydrogen peroxide-resistant LNCaP derivatives (HPR50 cells) PDE4B was decreased and as a result PKA activity was increased. Moreover, PDE4B expression was reduced in advanced prostate cancer and PDE4B knockdown promoted castration-resistant growth of LNCaP cells.
CONCLUSIONS
Oxidative stress may suppress PDE4B expression and activate the PKA pathway. The PDE4B/PKA pathway contributed to progression of androgen-dependent prostate cancer to CRPC. This pathway may represent an attractive therapeutic molecular target. Prostate 72:741–751, 2012. © 2011 Wiley Periodicals, Inc.
REFERENCES
- 1 Garzotto M, Myrthue A, Higano CS, Beer TM. Neoadjuvant mitoxantrone and docetaxel for high-risk localized prostate cancer. Urol Oncol 2006; 24: 254–259.
- 2 Kung HJ, Evans CP. Oncogenic activation of androgen receptor. Urol Oncol 2009; 27(1): 48–52.
- 3 Kim J, Jia L, Stallcup M, Coetzee G. The role of protein kinase A pathway and cAMP responsive element-binding protein in androgen receptor-mediated transcription at the prostate-specific antigen locus. J Mol Endocrinol 2005; 34(1): 107–118.
- 4 Tam L, McGlynn LM, Traynor P, Mukherjee R, Bartlett JMS, Edwards J. Expression levels of the JAK/STAT pathway in the transition from hormone-sensitive to hormone-refractory prostate cancer. Br J Cancer 2007; 97(3): 378–383.
- 5 Ueda T, Bruchovsky N, Sadar MD. Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways. J Biol Chem 2002; 277(9): 7076–7085.
- 6 Wang G, Jones S, Marra M, Sadar M. Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells. Oncogene 2006; 25(55): 7311–7323.
- 7 Merkle D, Hoffmann R. Roles of cAMP and cAMP-dependent protein kinase in the progression of prostate cancer: Cross-talk with the androgen receptor. Cell Signal 2011; 23(3): 507–515.
- 8 Bradbury A, Carter D, Miller W, Cho-Chung Y, Clair T. Protein kinase A (PK-A) regulatory subunit expression in colorectal cancer and related mucosa. Br J Cancer 1994; 69(4): 738–742.
- 9 Miller W, Hulme M, Cho-Chung Y, Elton R. Types of cyclic AMP binding proteins in human breast cancers. Eur J Cancer 1993; 29(7): 989–991.
- 10 Khor L, Bae K, Al-Saleem T, Hammond E, Grignon D, Sause W, Pilepich M, Okunieff P, Sandler H, Pollack A. Protein kinase A RI-[alpha] predicts for prostate cancer outcome: Analysis of Radiation Therapy Oncology Group Trial 86-10. Int J Radiat Oncol Biol Phys 2008; 71(5): 1309–1315.
- 11 James MA, Lu Y, Liu Y, Vikis HG, You M. RGS17, an overexpressed gene in human lung and prostate cancer, induces tumor cell proliferation through the cyclic AMP-PKA-CREB pathway. Cancer Res 2009; 69(5): 2108–2116.
- 12 Kasbohm EA, Guo R, Yowell CW, Bagchi G, Kelly P, Arora P, Casey PJ, Daaka Y. Androgen receptor activation by Gs signaling in prostate cancer cells. J Biol Chem 2005; 280(12): 11583–11589.
- 13 Xie Y, Wolff DW, Lin MF, Tu Y. Vasoactive intestinal peptide transactivates the androgen receptor through a protein kinase A-dependent extracellular signal-regulated kinase pathway in prostate cancer LNCaP cells. Mol Pharmacol 2007; 72(1): 73–85.
- 14 Sadar M. Androgen-independent induction of prostate-specific antigen gene expression via cross-talk between the androgen receptor and protein kinase A signal transduction pathways. J Biol Chem 1999; 274(12): 7777–7783.
- 15 Bagchi G, Wu J, French J, Kim J, Moniri NH, Daaka Y. Androgens transduce the Gαs-mediated activation of protein kinase A in prostate cells. Cancer Res 2008; 68(9): 3225–3231.
- 16 Ckert S, Oelke M, Stief C, Andersson K, Jonas U, Hedlund P. Immunohistochemical distribution of cAMP-and cGMP-phosphodiesterase (PDE) isoenzymes in the human prostate. Eur Urol 2006; 49(4): 740–745.
- 17 Shiota M, Yokomizo A, Tada Y, Inokuchi J, Kashiwagi E, Masubuchi D, Eto M, Uchiumi T, Naito S. Castration resistance of prostate cancer cells caused by castration-induced oxidative stress through Twist1 and androgen receptor overexpression. Oncogene 2010; 29(2): 237–250.
- 18 Kashiwagi E, Izumi H, Yasuniwa Y, Baba R, Doi Y, Kidani A, Arao T, Nishio K, Naito S, Kohno K. Enhanced expression of nuclear factor I/B in oxaliplatin-resistant human cancer cell lines. Cancer Science 2011; 102(2): 382–386.
- 19 Shiota M, Izumi H, Onitsuka T, Miyamoto N, Kashiwagi E, Kidani A, Yokomizo A, Naito S, Kohno K. Twist promotes tumor cell growth through YB-1 expression. Cancer Res 2008; 68(1): 98–105.
- 20 Shiota M, Izumi H, Tanimoto A, Takahashi M, Miyamoto N, Kashiwagi E, Kidani A, Hirano G, Masubuchi D, Fukunaka Y. Programmed cell death protein 4 down-regulates Y-box binding protein-1 expression via a direct interaction with Twist1 to suppress cancer cell growth. Cancer Res 2009; 69(7): 3148–3156.
- 21
Nesterova MV,
Cho-Chung YS.
Significance of protein kinase A in cancer.
Apoptosis Cell Signaling Hum Dis
2007;
1:
3–30.
10.1007/978-1-59745-199-4_1 Google Scholar
- 22 Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer 2001; 1(1): 34–45.
- 23 Gioeli D, Ficarro SB, Kwiek JJ, Aaronson D, Hancock M, Catling AD, White FM, Christian RE, Settlage RE, Shabanowitz J. Androgen receptor phosphorylation. J Biol Chem 2002; 277(32): 29304–29314.
- 24 Nazareth L, Weigel N. Activation of the human androgen receptor through a protein kinase A signaling pathway. J Biol Chem 1996; 271(33): 19900–19907.
- 25 Mosch HU, Kubler E, Krappmann S, Fink GR, Braus GH. Crosstalk between the Ras2p-controlled mitogen-activated protein kinase and cAMP pathways during invasive growth of Saccharomyces cerevisiae . Mol Biol Cell 1999; 10(5): 1325–1335.
- 26 Choi JH, Choi KC, Auersperg N, Leung PCK. Gonadotropins activate proteolysis and increase invasion through protein kinase A and phosphatidylinositol 3-kinase pathways in human epithelial ovarian cancer cells. Cancer Res 2006; 66(7): 3912–3920.
- 27 Bodenstine TM, Vaidya KS, Ismail A, Beck BH, Cook LM, Diers AR, Landar A, Welch DR. Homotypic gap junctional communication associated with metastasis suppression increases with PKA activity and is unaffected by PI3K inhibition. Cancer Res 2010; 70(23): 10002–10011.
- 28 Houslay MD. PDE4 cAMP-specific phosphodiesterases. Prog Nucleic Acid Res Mol Biol 2001; 69: 249–315.
- 29 Houslay MD, Adams DR. PDE4 cAMP phosphodiesterases: Modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J 2003; 370 (Pt 1): 1–18.
- 30 Houslay MD, Schafer P, Zhang KYJ. Keynote review: Phosphodiesterase-4 as a therapeutic target. Drug Discov Today 2005; 10(22): 1503–1519.
- 31 Smith PG, Wang F, Wilkinson KN, Savage KJ, Klein U, Neuberg DS, Bollag G, Shipp MA, Aguiar RCT. The phosphodiesterase PDE4B limits cAMP-associated PI3K/AKT-dependent apoptosis in diffuse large B-cell lymphoma. Blood 2005; 105(1): 308–316.
- 32 Marko D, Pahlke G, Merz KH, Eisenbrand G. Cyclic 3′,5′-nucleotide phosphodiesterases: Potential targets for anticancer therapy. Chem Res Toxicol 2000; 13(10): 944–948.
- 33 Narita M, Murata T, Shimizu K, Nakagawa T, Sugiyama T, Inui M, Hiramoto K, Tagawa T. A role for cyclic nucleotide phosphodiesterase 4 in regulation of the growth of human malignant melanoma cells. Oncol Rep 2007; 17(5): 1133–1139.
- 34 Goldhoff P, Warrington NM, Limbrick DD, Hope A, Woerner BM, Jackson E, Perry A, Piwnica-Worms D, Rubin JB. Targeted inhibition of cyclic AMP phosphodiesterase-4 promotes brain tumor regression. Clin Cancer Res 2008; 14(23): 7717–7725.
- 35 Rahrmann EP, Collier LS, Knutson TP, Doyal ME, Kuslak SL, Green LE, Malinowski RL, Roethe L, Akagi K, Waknitz M. Identification of PDE4D as a proliferation promoting factor in prostate cancer using a Sleeping Beauty transposon-based somatic mutagenesis screen. Cancer Res 2009; 69(10): 4388–4396.
- 36 Moon EY, Lerner A. PDE4 inhibitors activate a mitochondrial apoptotic pathway in chronic lymphocytic leukemia cells that is regulated by protein phosphatase 2A. Blood 2003; 101(10): 4122–4130.
- 37 Ogawa R, Streiff M, Bugayenko A, Kato G. Inhibition of PDE4 phosphodiesterase activity induces growth suppression, apoptosis, glucocorticoid sensitivity, p53, and p21 (WAF1/CIP1) proteins in human acute lymphoblastic leukemia cells. Blood 2002; 99(9): 3390–3397.
- 38 Amorino GP, Parsons SJ. Neuroendocrine cells in prostate cancer. Crit Rev Eukaryot Gene Expr 2004; 14(4): 287–300.
- 39 Bang Y, Pirnia F, Fang W, Kang W, Sartor O, Whitesell L, Ha M, Tsokos M, Sheahan M, Nguyen P. Terminal neuroendocrine differentiation of human prostate carcinoma cells in response to increased intracellular cyclic AMP. Proc Natl Acad Sci USA 1994; 91(12): 5330–5334.
- 40 Cox ME, Deeble PD, Lakhani S, Parsons SJ. Acquisition of neuroendocrine characteristics by prostate tumor cells is reversible. Cancer Res 1999; 59(15): 3821–3830.
- 41 Kvissel AK, Ramberg H, Eide T, Svindland A, Skålhegg BS, Taskén KA. Androgen dependent regulation of protein kinase A subunits in prostate cancer cells. Cell Signal 2007; 19(2): 401–409.
- 42 Kumar B, Koul S, Khandrika L, Meacham RB, Koul HK. Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype. Cancer Res 2008; 68(6): 1777–1785.
- 43 Chen L, Stacewicz-Sapuntzakis M, Duncan C, Sharifi R, Ghosh L, Breemen R, Ashton D, Bowen PE. Oxidative DNA damage in prostate cancer patients consuming tomato sauce-based entrees as a whole-food intervention. JNCI J Natl Cancer Inst 2001; 93(24): 1872–1879.
- 44 McCord J. Superoxide radical: Controversies, contradictions, and paradoxes. Proc Soc Exp Biol 1995; 209(2): 112–117.
- 45 Martin K, Barrett J. Reactive oxygen species as double-edged swords in cellular processes: Low-dose cell signaling versus high-dose toxicity. Hum Exp Toxicol 2002; 21(2): 71–75.
