Neuroendocrine Differentiation and Epithelial to Mesenchymal Transition in Prostate Cancer: cAMP-Dependent Signaling as a Therapeutic Target

• Charles E. Myers

  Foundation for Cancer Research and Education, 690 Bent Oaks Drive, Earlysville, VA 22936, USA

 Prostate cancer exhibits both epithelial to mesenchymal transition and neuroendocrine differentiation. The major barrier to targeting epithelial to mesenchymal transition is that it is heavily involved with normal biology, such as wound repair. In prostate cancer, cAMP can trigger both neuroendocrine differentiation and epithelial to mesenchymal transition in a Snail-dependent manner We will review inhibition of cAMP-signaling as a target for drug development with the goal of simultaneously blocking both neuroendocrine differentiation and epithelial to mesenchymal transition in a tissue and tumor selective manner.

Crawford ED, Eisenberger MA, McLeod DG, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 1989; 321: 419-424. http://dx.doi.org/10.1056/NEJM198908173210702

Cerasuolo M, Paris D, Iannotti FA, et al. Neuroendocrine Transdifferentiation in Human Prostate Cancer Cells: An Integrated Approach. Cancer Res 2015; 75: 2975-2986. http://dx.doi.org/10.1158/0008-5472.CAN-14-3830

Berman-Booty LD, Knudsen KE. Models of neuroendocrine prostate cancer. Endocr Relat Cancer 2015; 22: R33-49. http://dx.doi.org/10.1530/ERC-14-0393

Parimi V, Goyal R, Poropatich K, Yang XJ. Neuroendocrine differentiation of prostate cancer: a review. Am J Clin Exp Urol 2014; 2: 273-285.

Eric Jay Small JH, Jack Youngren et al. Characterization of neuroendocrine prostate cancer (NEPC) in patients with metastatic castration resistant prostate cancer (mCRPC) resistant to abiraterone (Abi) or enzalutamide (Enz): Preliminary results from the SU2C/PCF/AACR West Coast Prostate Cancer Dream Team (WCDT). J Clin Oncol 2014; 32: (suppl 4; abstr 79).

Small EJ, Huang J, Youngren J, et al. Characterization of neuroendocrine prostate cancer (NEPC) in patients with metastatic castration resistant prostate cancer (mCRPC) resistant to abiraterone (Abi) or enzalutamide (Enz): Preliminary results from the SU2C/PCF/AACR West Coast Prostate Cancer Dream Team (WCDT). J Clin Oncol 2015; 33: (suppl; abstr 5003).

Beltran H, Prandi H, Mosquera JM, et al. Defining a molecular subclass of treatment resistant prostate cancer. J Clin Oncol 2015; 33: (suppl; abstr 5004)

Yuan TC, Veeramani S, Lin FF, et al. Androgen deprivation induces human prostate epithelial neuroendocrine differentiation of androgen-sensitive LNCaP cells. Endocr Relat Cancer 2006; 13: 151-167. http://dx.doi.org/10.1677/erc.1.01043

Jongsma J, Oomen MH, Noordzij MA, et al. Androgen-independent growth is induced by neuropeptides in human prostate cancer cell lines. Prostate 2000; 42: 34-44. http://dx.doi.org/10.1002/(SICI)1097-0045(20000101)42:1<34::AID-PROS5>3.0.CO;2-2

Bang YJ, Pirnia F, Fang WG, et al. Terminal neuroendocrine differentiation of human prostate carcinoma cells in response to increased intracellular cyclic AMP. Proc Natl Acad Sci USA 1994; 91: 5330-5334. http://dx.doi.org/10.1073/pnas.91.12.5330

Cox ME, Deeble PD, Lakhani S, Parsons SJ. Acquisition of neuroendocrine characteristics by prostate tumor cells is reversible: implications for prostate cancer progression. Cancer Res 1999; 59: 3821-3830.

Cox ME, Deeble PD, Bissonette EA, Parsons SJ. Activated 3’,5’-cyclic AMP-dependent protein kinase is sufficient to induce neuroendocrine-like differentiation of the LNCaP prostate tumor cell line. J Biol Chem 2000; 275: 13812-13818. http://dx.doi.org/10.1074/jbc.275.18.13812

Deeble PD, Cox ME, Frierson HF, et al. Androgen-independent growth and tumorigenesis of prostate cancer cells are enhanced by the presence of PKA-differentiated neuroendocrine cells. Cancer Res 2007; 67: 3663-3672. http://dx.doi.org/10.1158/0008-5472.CAN-06-2616

Alberti C. Neuroendocrine differentiation in prostate carcinoma: focusing on its pathophysiologic mechanisms and pathological features. G Chir 2010; 31: 568-574.

Jones SE, Palmer TM. Protein kinase A-mediated phosphorylation of RhoA on serine 188 triggers the rapid induction of a neuroendocrine-like phenotype in prostate cancer epithelial cells. Cell Signal 2012; 24: 1504-1514. http://dx.doi.org/10.1016/j.cellsig.2012.03.018

McKeithen D, Graham T, Chung LW, Odero-Marah V. Snail transcription factor regulates neuroendocrine differentiation in LNCaP prostate cancer cells. Prostate 2010; 70: 982-992. http://dx.doi.org/10.1002/pros.21132

Smith BN, Odero-Marah VA. The role of Snail in prostate cancer. Cell Adh Migr 2012; 6: 433-441. http://dx.doi.org/10.4161/cam.21687

Bang YJ, Kim SJ, Danielpour D, et al. Cyclic AMP induces transforming growth factor beta 2 gene expression and growth arrest in the human androgen-independent prostate carcinoma cell line PC-3. Proc Natl Acad Sci USA 1992; 89: 3556-3560. http://dx.doi.org/10.1073/pnas.89.8.3556

Kokudo T, Suzuki Y, Yoshimatsu Y, Yamazaki T, Watabe T, Miyazono K. Snail is required for TGFbeta-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells. J Cell Sci 2008; 121: 3317-3324. http://dx.doi.org/10.1242/jcs.028282

MacPherson MR, Molina P, Souchelnytskyi S, et al. Phosphorylation of serine 11 and serine 92 as new positive regulators of human Snail1 function: potential involvement of casein kinase-2 and the cAMP-activated kinase protein kinase A. Mol Biol Cell 2010; 21: 244-253. http://dx.doi.org/10.1091/mbc.E09-06-0504

Rinaldi L, Sepe M, Donne RD, Feliciello A. A dynamic interface between ubiquitylation and cAMP signaling. Front Pharmacol 2015; 6: 177. http://dx.doi.org/10.3389/fphar.2015.00177

Cho-Chung YS, Nesterova MV. Tumor reversion: protein kinase A isozyme switching. Ann NY Acad Sci 2005; 1058: 76-86. http://dx.doi.org/10.1196/annals.1359.014

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: 401-409. http://dx.doi.org/10.1016/j.cellsig.2006.07.011

Neary CL, Cho-Chung YS. Nuclear translocation of the catalytic subunit of protein kinase A induced by an antisense oligonucleotide directed against the RIalpha regulatory subunit. Oncogene 2001; 20: 8019-8024. http://dx.doi.org/10.1038/sj.onc.1204992

Nesterova M, Noguchi K, Park YG, Lee YN, Cho-Chung YS. Compensatory stabilization of RIIbeta protein, cell cycle deregulation, and growth arrest in colon and prostate carcinoma cells by antisense-directed down-regulation of protein kinase A RIalpha protein. Clin Cancer Res 2000; 6: 3434-3441.

Cho YS, Cho-Chung YS. Antisense protein kinase A RIalpha acts synergistically with hydroxycamptothecin to inhibit growth and induce apoptosis in human cancer cells: molecular basis for combinatorial therapy. Clin Cancer Res 2003; 9: 1171-1178.

Chiriva-Internati M, Yu Y, Mirandola L, et al. Identification of AKAP-4 as a new cancer/testis antigen for detection and immunotherapy of prostate cancer. Prostate 2012; 72: 12-23. http://dx.doi.org/10.1002/pros.21400

Akamine P, Madhusudan, Brunton LL, et al. Balanol analogues probe specificity determinants and the conformational malleability of the cyclic 3’,5’-adenosine monophosphate-dependent protein kinase catalytic subunit. Biochemistry 2004; 43: 85-96. http://dx.doi.org/10.1021/bi035042p

Gustafsson AB, Brunton LL. Differential and selective inhibition of protein kinase A and protein kinase C in intact cells by balanol congeners. Mol Pharmacol 1999; 56: 377-382.

Pande V, Ramos MJ, Gago F. The Protein kinase inhibitor balanol: structure-activity relationships and structure-based computational studies. Anticancer Agents Med Chem 2008; 8: 638-645. http://dx.doi.org/10.2174/187152008785133056

Wong CF, Hünenberger PH, Akamine P, et al. Computational analysis of PKA-balanol interactions. J Med Chem 2001; 44: 1530-1539. http://dx.doi.org/10.1021/jm000443d

Kamenetsky M, Middelhaufe S, Bank EM, Levin LR, Buck J, Steegborn C. Molecular details of cAMP generation in mammalian cells: a tale of two systems. J Mol Biol 2006; 362: 623-639. http://dx.doi.org/10.1016/j.jmb.2006.07.045

Iwatsubo K, Tsunematsu T, Ishikawa Y. Isoform-specific regulation of adenylyl cyclase: a potential target in future pharmacotherapy. Expert Opin Ther Targets 2003; 7: 441-451. http://dx.doi.org/10.1517/14728222.7.3.441

Patel TB, Du Z, Pierre S, Cartin L, Scholich K. Molecular biological approaches to unravel adenylyl cyclase signaling and function. Gene 2001; 269: 13-25. http://dx.doi.org/10.1016/S0378-1119(01)00448-6

Kleinboelting S, Diaz A, Moniot S, et al. Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate. Proc Natl Acad Sci USA 2014; 111: 3727-3732. http://dx.doi.org/10.1073/pnas.1322778111

Steegborn C. Structure, mechanism, and regulation of soluble adenylyl cyclases - similarities and differences to transmembrane adenylyl cyclases. Biochim Biophys Acta 2014; 1842: 2535-2547. http://dx.doi.org/10.1016/j.bbadis.2014.08.012

Flacke JP, Flacke H, Appukuttan A, et al. Type 10 soluble adenylyl cyclase is overexpressed in prostate carcinoma and controls proliferation of prostate cancer cells. J Biol Chem 2013; 288: 3126-3135. http://dx.doi.org/10.1074/jbc.M112.403279

Appukuttan A, Flacke JP, Flacke H, Posadowsky A, Reusch HP, Ladilov Y. Inhibition of soluble adenylyl cyclase increases the radiosensitivity of prostate cancer cells. Biochim Biophys Acta 2014; 1842: 2656-2663. http://dx.doi.org/10.1016/j.bbadis.2014.09.008

Brand CS, Hocker HJ, Gorfe AA, Cavasotto CN, Dessauer CW. Isoform selectivity of adenylyl cyclase inhibitors: characterization of known and novel compounds. J Pharmacol Exp Ther 2013; 347: 265-275. http://dx.doi.org/10.1124/jpet.113.208157

Byrne AM, Elliott C, Hoffmann R, Baillie GS. The activity of cAMP-phosphodiesterase 4D7 (PDE4D7) is regulated by protein kinase A-dependent phosphorylation within its unique N-terminus. FEBS Lett 2015; 589: 750-755. http://dx.doi.org/10.1016/j.febslet.2015.02.004

Henderson DJ, Byrne A, Dulla K, et al. The cAMP phosphodiesterase-4D7 (PDE4D7) is downregulated in androgen-independent prostate cancer cells and mediates proliferation by compartmentalising cAMP at the plasma membrane of VCaP prostate cancer cells. Br J Cancer 2014; 110: 1278-1287. http://dx.doi.org/10.1038/bjc.2014.22

• PDF