Inhibition of breast cancer cell migration by activation of cAMP signaling
- 1k Downloads
Almost all deaths from breast cancer arise from metastasis of the transformed cells to other sites in the body. Hence, uncovering a means of inhibiting breast cancer cell migration would provide a significant advance in the treatment of this disease. Stimulation of the cAMP signaling pathway has been shown to inhibit migration and motility of a number of cell types. A very effective way of selectively stimulating cAMP signaling is through inhibition of cyclic nucleotide phosphodiesterases (PDEs). Therefore, we examined full expression profiles of all known PDE genes at the mRNA and protein levels in four human breast cancer cell lines and eight patients’ breast cancer tissues. By these analyses, expression of almost all PDE genes was seen in both cell lines and tissues. In the cell lines, appreciable expression was seen for PDEs 1C, 2A, 3B, 4A, 4B, 4D, 5A, 6B, 6C, 7A, 7B, 8A, 9A, 10A, and 11A. In patients’ tissues, appreciable expression was seen for PDEs 1A, 3B, 4A, 4B, 4C, 4D, 5A, 6B, 6C, 7A, 7B, 8A, 8B, and 9A. PDE8A mRNA in particular is prominently expressed in all cell lines and patients’ tissue samples examined. We show here that stimulation of cAMP signaling with cAMP analogs, forskolin, and PDE inhibitors, including selective inhibitors of PDE3, PDE4, PDE7, and PDE8, inhibit aggressive triple negative MDA-MB-231 breast cancer cell migration. Under the same conditions, these agents had little effect on breast cancer cell proliferation. This study demonstrates that PDE inhibitors inhibit breast cancer cell migration, and thus may be valuable therapeutic targets for inhibition of breast cancer metastasis. Since PDE8A is expressed in all breast cancer samples, and since dipyridamole, which inhibits PDE8, and PF-04957325, a selective PDE8 inhibitor, both inhibit migration, it suggests that PDE8A may be a valuable novel target for treatment of this disease.
KeywordsBreast cancer Cyclic nucleotide phosphodiesterase Cell migration cAMP signaling
The authors acknowledge support for this work by Grants from the Smart Family Foundation, the Connecticut Breast Health Initiative Inc., the State of Connecticut Department of Public Health, and the National Multiple Sclerosis Society. PE dedicates this paper in memory of his sweet, beautiful, loving daughter, Serena Rae Epstein (March 22, 1984–July 1, 2011), who has been and continues to be his inspiration for everything he does.
Conflict of interest
The authors declare that they have no conflict of interest.
The authors declare that all experiments reported in this publication were performed in compliance with all current laws and regulations of the United States of America.
- 7.Burdyga A, Conant A, Haynes L, Zhang J, Jalink K, Sutton R, Neoptolemos J, Costello E, Tepikin A (2013) cAMP inhibits migration, ruffling and paxillin accumulation in focal adhesions of pancreatic ductal adenocarcinoma cells: effects of PKA and EPAC. Biochim Biophys Acta 1833:2664–2672. doi: 10.1016/j.bbamcr.2013.06.011 CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Ou Y, Zheng X, Gao Y, Shu M, Leng T, Li Y, Yin W, Zhu W, Huang Y, Zhou Y, Tang J, Qiu P, Yan G, Hu J, Ruan H, Hu H (2014) Activation of cyclic AMP/PKA pathway inhibits bladder cancer cell invasion by targeting MAP4-dependent microtubule dynamics. Urol Oncol 32:47. e21–47. e48. doi: 10.1016/j.urolonc.2013.06.017 CrossRefGoogle Scholar
- 20.McEwan DG, Brunton VG, Baillie GS, Leslie NR, Houslay MD, Frame MC (2007) Chemoresistant KM12C colon cancer cells are addicted to low cyclic AMP levels in a phosphodiesterase 4-regulated compartment via effects on phosphoinositide 3-kinase. Cancer Res 67:5248–5257. doi: 10.1158/0008-5472.CAN-07-0097 CrossRefPubMedGoogle Scholar
- 22.Clarysse L, Gueguinou M, Potier-Cartereau M, Vandecasteele G, Bougnoux P, Chevalier S, Chantome A, Vandier C (2014) cAMP-PKA inhibition of SK3 channel reduced both Ca(2+) entry and cancer cell migration by regulation of SK3-Orai1 complex. Pflugers Arch 466:1921–1932. doi: 10.1007/s00424-013-1435-5 CrossRefPubMedGoogle Scholar
- 27.Serrels B, Sandilands E, Serrels A, Baillie G, Houslay MD, Brunton VG, Canel M, Machesky LM, Anderson KI, Frame MC (2010) A complex between FAK, RACK1, and PDE4D5 controls spreading initiation and cancer cell polarity. Curr Biol 20:1086–1092. doi: 10.1016/j.cub.2010.04.042 CrossRefPubMedGoogle Scholar
- 31.Brown KM, Day JP, Huston E, Zimmermann B, Hampel K, Christian F, Romano D, Terhzaz S, Lee LC, Willis MJ, Morton DB, Beavo JA, Shimizu-Albergine M, Davies SA, Kolch W, Houslay MD, Baillie GS (2013) Phosphodiesterase-8A binds to and regulates Raf-1 kinase. Proc Natl Acad Sci USA 110:E1533–E1542. doi: 10.1073/pnas.1303004110 CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Terry R, Cheung YF, Praestegaard M, Baillie GS, Huston E, Gall I, Adams DR, Houslay MD (2003) Occupancy of the catalytic site of the PDE4A4 cyclic AMP phosphodiesterase by rolipram triggers the dynamic redistribution of this specific isoform in living cells through a cyclic AMP independent process. Cell Signal 15:955–971. doi: 10.1016/S0898-6568(03)00092-5 CrossRefPubMedGoogle Scholar
- 38.Christian F, Anthony DF, Vadrevu S, Riddell T, Day JP, McLeod R, Adams DR, Baillie GS, Houslay MD (2010) p62 (SQSTM1) and cyclic AMP phosphodiesterase-4A4 (PDE4A4) locate to a novel, reversible protein aggregate with links to autophagy and proteasome degradation pathways. Cell Signal 22:1576–1596. doi: 10.1016/j.cellsig.2010.06.003 CrossRefPubMedGoogle Scholar
- 39.Day JP, Lindsay B, Riddell T, Jiang Z, Allcock RW, Abraham A, Sookup S, Christian F, Bogum J, Martin EK, Rae RL, Anthony D, Rosair GM, Houslay DM, Huston E, Baillie GS, Klussmann E, Houslay MD, Adams DR (2011) Elucidation of a structural basis for the inhibitor-driven, p62 (SQSTM1)-dependent intracellular redistribution of cAMP phosphodiesterase-4A4 (PDE4A4). J Med Chem 54:3331–3347. doi: 10.1021/jm200070e CrossRefPubMedGoogle Scholar
- 41.American Cancer Society (2015) Breast cancer key statistics. American Cancer Society, Atlanta. http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-key-statistics. Accessed 20 May 2015
- 46.Nome T, Thomassen GO, Bruun J, Ahlquist T, Bakken AC, Hoff AM, Rognum T, Nesbakken A, Lorenz S, Sun J, Barros-Silva JD, Lind GE, Myklebost O, Teixeira MR, Meza-Zepeda LA, Lothe RA, Skotheim RI (2013) Common fusion transcripts identified in colorectal cancer cell lines by high-throughput RNA sequencing. Transl Oncol 6:546–553. doi: 10.1593/tlo.13457 CrossRefPubMedPubMedCentralGoogle Scholar
- 47.Tinsley HN, Gary BD, Keeton AB, Lu W, Li Y, Piazza GA (2011) Inhibition of PDE5 by sulindac sulfide selectively induces apoptosis and attenuates oncogenic Wnt/beta-catenin-mediated transcription in human breast tumor cells. Cancer Prev Res 4:1275–1284. doi: 10.1158/1940-6207.CAPR-11-0095 CrossRefGoogle Scholar
- 52.Spina A, Di Maiolo F, Esposito A, Sapio L, Chiosi E, Sorvillo L, Naviglio S (2012) cAMP elevation down-regulates beta3 integrin and focal adhesion kinase and inhibits leptin-induced migration of MDA-MB-231 breast cancer cells. BioRes Open Access 1:324–332. doi: 10.1089/biores.2012.0270 CrossRefPubMedPubMedCentralGoogle Scholar
- 59.Spano D, Marshall JC, Marino N, De Martino D, Romano A, Scoppettuolo MN, Bello AM, Di Dato V, Navas L, De Vita G, Medaglia C, Steeg PS, Zollo M (2013) Dipyridamole prevents triple-negative breast-cancer progression. Clin Exp Metastasis 30:47–68. doi: 10.1007/s10585-012-9506-0 CrossRefPubMedGoogle Scholar