Cancer and Metastasis Reviews

, Volume 37, Issue 2–3, pp 245–255 | Cite as

The role of lipid signaling in the progression of malignant melanoma

  • József TímárEmail author
  • B. Hegedüs
  • E. Rásó


In the past decades, a vast amount of data accumulated on the role of lipid signaling pathways in the progression of malignant melanoma, the most metastatic/aggressive human cancer type. Genomic studies identified that PTEN loss is the leading factor behind the activation of the PI3K-signaling pathway in melanoma, mutations of which are one of the main resistance mechanisms behind target therapy failures. On the other hand, illegitimate expressions of megakaryocytic genes p12-lipoxyganse, cyclooxygenase-2, and phosphodiestherase-2/autotaxin (ATX) are mostly involved in the regulation of motility signaling in melanoma through various G-protein-coupled bioactive lipid receptors. Furthermore, endocannabinoid signaling can also be a novel paracrine survival factor in melanoma. Last but not least, prenylation inhibitors acting even on mutated small GTP-ases, such as NRAS of melanoma may offer novel therapeutic opportunities. As regards melanoma, the most effective therapy nowadays is immunotherapy, with the resistance mechanisms also possibly involving the lipid signaling activities of melanoma cells, which further supports the idea of their being therapeutic targets.


Eicosanoid Signaling Melanoma Cyclooxygenase Lipoxygenase Phosphodiestherase-2 



Arachidonic acid


Autocrine motility factor






Ectonucleotide pyrophosphatase


Farnesyl transferase


Geranylgeranyl transferase


G-protein-coupled receptor


Histone deacetylase


Hydroxy tetraenoic acid




Matrix metalloproteinase


Next-generation sequencing




PI3 kinase




Prostaglandin synthase


Poly-unsaturated fatty acid


Platelet-type 12-LOX


Receptor tyrosine kinase


Zoledronic acid



This work was supported by the National R&D& Innovation Office, Hungary (NKFI-K-112371, NVKP-16-1-2016-0004 and -0020, NAPB/KTIA13-0021).


  1. 1.
    Timar, J., Vizkeleti, L., Doma, V., Barbai, T., & Rásó, E. (2016). Genetic progression of malignant melanoma. Cancer Metastasis Reviews, 35, 93–107.CrossRefPubMedGoogle Scholar
  2. 2.
    Welsh, S. J., Rizos, H., Scolyer, R. A., & Long, G. V. (2016). Resistance to combination BRAF and MEK inhibition in metastatic melanoma: where to next? European Journal of Cancer, 62, 76–85.CrossRefPubMedGoogle Scholar
  3. 3.
    Hayward, N. K., Wilmott, J. S., Waddell, N., Johansson, P. A., Field, M. A., Nones, K., Patch, A. M., Kakavand, H., Alexandrov, L. B., Burke, H., Jakrot, V., Kazakoff, S., Holmes, O., Leonard, C., Sabarinathan, R., Mularoni, L., Wood, S., Xu, Q., Waddell, N., Tembe, V., Pupo, G. M., de Paoli-Iseppi, R., Vilain, R. E., Shang, P., Lau, L. M. S., Dagg, R. A., Schramm, S. J., Pritchard, A., Dutton-Regester, K., Newell, F., Fitzgerald, A., Shang, C. A., Grimmond, S. M., Pickett, H. A., Yang, J. Y., Stretch, J. R., Behren, A., Kefford, R. F., Hersey, P., Long, G. V., Cebon, J., Shackleton, M., Spillane, A. J., Saw, R. P. M., López-Bigas, N., Pearson, J. V., Thompson, J. F., Scolyer, R. A., & Mann, G. J. (2017). Whole-genome landscapes of major melanoma subtypes. Nature, 545, 175–180.CrossRefPubMedGoogle Scholar
  4. 4.
    Timar, J., Tóvári, J., Rásó, E., Mészáros, L., Bereczky, B., & Lapis, K. (2005). Platelet mimicry of cancer cells: epiphenomenon with clinical significance. Oncology, 69, 185–201.CrossRefPubMedGoogle Scholar
  5. 5.
    Kenessei, I., Bánki, B., Márk, A., Varga, N., Tóvári, J., et al. (2012). Revisiting CB1 receptor as drug target in human melanoma. Pathology Oncology Research, 18, 857–866.CrossRefGoogle Scholar
  6. 6.
    Ullah, N., Mansha, M., & Casey, P. J. (2016). Protein geranylgeranyltransferase type 1 as a target in cancer. Current Cancer Drug Targets, 16, 563–571.CrossRefPubMedGoogle Scholar
  7. 7.
    Garay, T., Kenessey, I., Molnár, E., Juhász, E., Réti, A., et al. (2015). Prenylation-induced cell death in melanoma: reduced sensitivity in BRAF mutant/PTEN wild-type melanoma cells. PLoS One, 10, e0117021.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Franklin, C., Livingstone, E., Riesch, A., Schilling, B., & Schadendorf, D. (2017). Immunotherapy in melanoma: recent advances and future directions. European Journal of Surgical Oncology, 43, 604–611.CrossRefPubMedGoogle Scholar
  9. 9.
    Gide, T. N., Wilmott, J. S., Scolyer, R. A., & Long, G. V. (2018). Primary and acquired resistance to immune checkpoint inhibitors in metastatic melanoma. Clinical Cancer Research, 24, 1260–1270.CrossRefPubMedGoogle Scholar
  10. 10.
    Carlino, M. S., Long, G. V., Kefford, R. F., & Rizos, H. (2015). Targeting oncogenic BRAF and aberrant MAPK activation in the treatment of cutaneous melanoma. Critical Reviews in Oncology/Hematology, 96, 385–398.CrossRefPubMedGoogle Scholar
  11. 11.
    Kunz, M., & Hölzel, M. (2017). The impact of melanoma genetics on treatment response and resistance in clinical and experimental studies. Cancer Metastasis Reviews, 36, 53–75.CrossRefPubMedGoogle Scholar
  12. 12.
    Posch, C., Moslehi, H., Feeney, L., Green, G. A., Ebae, A., et al. (2013). Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo. PNAS, 110, 4015–4020.CrossRefPubMedGoogle Scholar
  13. 13.
    Gallagher, S. J., Gunatilake, D., Beaumont, K. A., Sharp, D. M., Tiffen, J. C., Heinemann, A., Weninger, W., Haass, N. K., Wilmott, J. S., Madore, J., Ferguson, P. M., Rizos, H., & Hersey, P. (2018). HDAC inhibitors restore BRAF-inhibitor sensitivity by altering PI3K and survival signalling in a subset of melanoma. International Journal of Cancer, 142, 1926–1937.CrossRefPubMedGoogle Scholar
  14. 14.
    Kim, S., Kim, H. T., & Suh, H. S. (2017). Combination therapy of BRAF inhibitors for advanced melanoma with BRAF V600 mutation: a systematic review and meta-analysis. Journal of Dermatological Treatment, 31, 1–8.Google Scholar
  15. 15.
    Xue, G., Romano, E., Massi, D., & Mandala, M. (2016). Wnt/b-catenin signaling in melanoma: preclinical rationale and novel therapeutic insights. Cancer Treatment Reviews, 49, 1–12.CrossRefPubMedGoogle Scholar
  16. 16.
    Serini, S., Zinzi, A., Ottes-Vasconcelos, R., Fasano, E., Rillo, M. G., et al. (2016). Role of β-catenin signaling in the anti-invasive effect of the omega-3 fatty acid DHA in human melanoma. Journal of Dermatological Science, 84, 149–159.CrossRefPubMedGoogle Scholar
  17. 17.
    Maresca, V., Flori, E., Camera, E., Bellei, B., Aspite, N., et al. (2013). Link ing αMSH with PPRγ in B16-F10 melanoma. Pigment Cell & Melanoma Research, 26, 113–127.CrossRefGoogle Scholar
  18. 18.
    Ribeling, C., Müller, C., & Geilen, C. C. (2003). Expression and regulation of phospholipase D isoenzymes in human melanoma cells and primary melanocytes. Melanoma Research, 13, 555–562.CrossRefGoogle Scholar
  19. 19.
    Oka, M., Hitomi, T., Okada, T., Nakamura, S., Nagai, H., et al. (2002). Dual regulation of phospholipase D1 by protein kinase C alpha in vivo. Biochemical and Biophysical Research Communications, 294, 1109–1113.CrossRefPubMedGoogle Scholar
  20. 20.
    Strache, M. L., Krutzch, H. C., Unsworth, E. J., Arestad, A., Cioce, C., et al. (1992). Identification purification and partial sequence analysis of autotaxin, a novel motility stimulating protein. The Journal of Biological Chemistry, 267, 2524–2529.Google Scholar
  21. 21.
    Watanabe, H., Carmi, P., Hogan, V., Raz, T., Siletti, S., et al. (1991). Purification of human tumor cell autocrine motility factor and molecular cloning of its receptor. The Journal of Biological Chemistry, 266, 13,442–13,448.Google Scholar
  22. 22.
    Jongsma, M., Matas-Rico, E., Rzadkowski, A., Jalink, K., & Moolenaar, W. H. (2011). LPA is a chemorepellent for B16 melanoma cells: action through the cAMP-elevating LPA5 receptor. PLoS One, 6, e29260.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Lee, S. C., Fujiwara, Y., Liu, J., Yue, J., Shimizu, Y., et al. (2014). Autotaxin and LPA1 and LPA5 receptors exert disparate functions in tumor cells versus the host tissue microenvironment in melanoma invasion and metastasis. Molecular Cancer Research, 13, 174–185.CrossRefPubMedGoogle Scholar
  24. 24.
    Oda, S. K., Strauch, P., Fujiwara, Y., Al-Shami, A., Oravecz, T., et al. (2013). Lysophosphatidic acid inhibits CD8 T cell activation and control of tumor progression. Cancer Immunology Research, 1, 245–255.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Altman, M. K., Gopal, V., Jia, W., Yu, S., Hall, H., et al. (2010). Targeting melanoma growth and viability reveals dualistic functionality of the phosphothionate analogue of carba cyclic phosphatidic acid. Molecular Cancer, 9, 140.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Susanto, O., YWH, K., Morrice, N., Tumanov, S., Thomason, P. A., et al. (2017). LPP3 mediates self-generation of chemotactic LPA gradients by melanoma cells. Journal of Cell Science, 130, 3455–3466.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Kurano, M., Miyagaki, T., Miyagawa, T., Igarashi, K., Shimamoto, S., Ikeda, H., Aoki, J., Sato, S., & Yatomi, Y. (2018). Association between serum autotaxin or phosphatidylserine-specific phospholipase A1 levels and melanoma. The Journal of Dermatology, 45, 571–579.CrossRefPubMedGoogle Scholar
  28. 28.
    Gupte, R., Patil, R., Liu, J., Wang, Y., lee, S. C., et al. (2011). Benzyl and naphthalene methylphosphonic acid inhibitors of autotaxin with anti-invasive and anti-metastatic activity. ChemMedChem, 6, 922–935.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Banerjee, S., Norman, D. D., Lee, S. C., Parrill, A. L., Pham, T. C., et al. Highly potent non-carboxylic acid autotaxin inhibitors reduce melanoma metastasis and chemotherapeutic resistance of breast cancer stam cells. Journal of Medicinal Chemistry, 60, 1309–1324.Google Scholar
  30. 30.
    Baba, Y., Funakoshi, T., Mori, M., Emoto, K., Masugi, Y., et al. (2017). Expression of monoacylglycerol lipase as a marker of tumor invasion and progression in malignant melanoma. Journal of the European Academy of Dermatology and Venereology, 31, 2038–2045.CrossRefPubMedGoogle Scholar
  31. 31.
    Lazar, I., Clement, E., Dauvillier, S., Milhas, D., Ducoux-Petit, M., et al. (2016). Adipocyte exosomes promote melanoma aggressiveness through fatty acid oxidation: a novel mechanism linking obesity and cancer. Cancer Research, 76, 4051–4057.CrossRefPubMedGoogle Scholar
  32. 32.
    Viswanathan, V. S., Zyan, M. J., Dhruv, H. D., Gill, S., Eichoff, O. M., et al. (2017). Dependency of therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature, 547, 453–457.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Goulet, A. C., Einsphar, J. G., Alberts, D. S., Beas, A., Burk, C., et al. (2003). Analysis of cyclooxygenase 2 (COX-2) expression during malignant melanoma progression. Cancer Biology & Therapy, 2, 713–718.CrossRefGoogle Scholar
  34. 34.
    Meyer, S., Fuchs, T. J., Bosserhoff, A. K., Hofstadter, F., Pauer, A., et al. (2012). A seven-marker signature and clinical outcome in malignant melanoma: a large-scale tissue-microarray study with two independent patient cohorts. PlosOne, 7, e38222.CrossRefGoogle Scholar
  35. 35.
    Kuzbicki, L., Lange, D., Stanek-Widera, A., & Chwirot, B. W. (2016). Intratumoral expression of cyclooxygenase-2 (COX-2) is a negative prognostic marker for patients with cutaneous melanoma. Melanoma Research, 26, 448–456.CrossRefPubMedGoogle Scholar
  36. 36.
    Panza, E., De Cicco, P., Ercolano, G., Amogida, C., Scognamiglio, G., et al. (2016). Differential expression of cyclooxygenase-2 in metastatic melanoma affects progression free survival. Oncotarget, 7, 57,077–57,085.CrossRefGoogle Scholar
  37. 37.
    Soares, C. D., Borges, C. F., Sena-Filho, M., Almeida, O. P., Stelini, R. F., et al. Prognostic significance of cyclooxygenase 2 and phosphorylated AKT1 overexpression in primary nonmetastatic and metastatic cutaneous melanomas. Melanoma Research, 27, 448–456.Google Scholar
  38. 38.
    Hennequart, M., Pilotte, L., Cane, S., Hoffmann, D., Stroobant, V., et al. (2017). Constitutive IDO1 expression in human tumors is driven by cyclooxygenase-2 and mediates intrinsic immune resistance. Cancer Immunology Research, 5, 695–709.CrossRefPubMedGoogle Scholar
  39. 39.
    Kim, S. H., Hashimoto, Y., Cho, S. N., Roszik, J., Milton, D. R., et al. (2016). Microsomal PGE2 synthase-1 regulates melanoma cell survival and associates with melanoma disease progression. Pigment Cell & Melanoma Research, 29, 297–308.CrossRefGoogle Scholar
  40. 40.
    Inada, M., Takita, M., Yokoyama, S., Watanabe, K., Tominari, T., et al. Direct melanoma cell contact induces stromal cell autocrine prostaglandin EP2-EP4 receptor signaling that drives tumor growth, angiogenesis and metastasis. The Journal of Biological Chemistry, 290, 29,781–29,793.Google Scholar
  41. 41.
    Zelenay, S., van der Veen, A. G., Böttcher, J. P., Snelgrove, K. J., Rogers, N., et al. (2015). Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell, 162, 1257–1270.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Botti, G., Fratangelo, F., Cerrone, M., Liquori, G., Cantile, M., et al. (2017). COX-2 expression positively correlates with PDL1 expression in human melanoma cells. Journal of Translational Medicine, 15, 46.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Seo, S. K., Seo, D. I., Park, W. S., Jung, W. K., Lee, D. S., et al. (2014). Attenuation of IFN-g-induced B7-H1 expression by 15-deoxy-delta(12,14)-prostaglandin J2 via downregulation of the JAK/STAT/IRF1 signaling pathway. Life Sciences, 112, 82–89.CrossRefPubMedGoogle Scholar
  44. 44.
    Neumann, S., Shirley, S. A., Kemp, R. A., & Hook, S. M. (2016). Improved antitumor activity of a therapeutic melanoma vaccine through the use of the dual COX2/5-LO inhibitor Licofelone. Frontiers in Immunology, 7, 537.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Vaid, M., Singh, T., Prasad, R., Kappes, J. C., & Katiyar, S. K. Therapeutic intervention of proanthocyanidins on the migration capacity of melanoma cells is mediated through PGE2 receptors and β-catenin signaling molecules. American Journal of Cancer Research, 5, 3325–3338.Google Scholar
  46. 46.
    Singh, T., & Katiyar, S. K. (2011). Green tee catechins reduce invasive potential of human melanoma cells by targeting COX-2, PGE2 receptors and epithelial-mesenchymal transition. PlosOne, 6, e25224.CrossRefGoogle Scholar
  47. 47.
    Gowda, R., Sharma, A., & Roberttson, G. P. (2017). Synergistic inhibitory effects of Celwexocib and Plumbagin on melanoma tumor growth. Cancer Letters, 385, 243–250.CrossRefPubMedGoogle Scholar
  48. 48.
    Rachidi, S., Wallace, K., Li, H., Lautenschlaeger, T., & Li, Z. (2018). Postdiagnostic aspirin use and overal survival in patients with melanoma. Journal of the American Academy of Dermatology, 78, 949–956.e1.CrossRefPubMedGoogle Scholar
  49. 49.
    Rásó, E., Tóvári, J., Tóth, K., Paku, S., Trikha, M., et al. (2001). Ectopic alphaIIb beta3 integrin signaling involves 12-lipoxygenase- and PKC-mediated serine phosphorylation events in melanoma cells. Thrombosis and Haemostasis, 85, 1037–1047.CrossRefPubMedGoogle Scholar
  50. 50.
    Silletti, S., Tímár, J., Honn, K. V., & Raz, A. (1994). Autocrine motility factor induces differential 12-lipoxygenase expression and activity in high- and low-metastatic K1735 melanoma cell variants. Cancer Research, 54, 5752–5756.PubMedGoogle Scholar
  51. 51.
    Tímár, J., Rásó, E., Honn, K. V., & Hagmann, W. (1999). 12-Lipoxygenase expression in human melanoma cell lines. Advances in Experimental Medicine and Biology, 469, 617–622.CrossRefPubMedGoogle Scholar
  52. 52.
    Rásó, E., Döme, B., Somlai, B., Zacharek, A., Hagmann, W., et al. (2004). Molecular identification, localisation and function of platelet-type 12-lipoxygenase in human melanoma progression under experimental and clinical conditions. Melanoma Research, 14, 245–250.CrossRefPubMedGoogle Scholar
  53. 53.
    Winer, I., Normolle, D. P., Shureiqi, I., Sondak, V. K., Johnson, T., et al. (2002). Expression of 12-lipoxygenase as a biomarker for melanoma carcinogenesis. Melanoma Research, 12, 429–434.CrossRefPubMedGoogle Scholar
  54. 54.
    Menter, D. G., Tucker, S. C., Kopetz, S., Sood, A. K., Crissman, J. D., & Honn, K. V. (2014). Platelets and cancer: a casual or causal relationship: revisited. Cancer Metastasis Reviews, 33, 231–269.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Timar, J., Chen, Y. Q., Liu, B., Bazaz, R., Talor, J. D., & Honn, K. V. (1992). The lipoxygenase metabolite 12(S)-HETE promotes aplphaIIb beta3 integrin-mediated tumor cell spreading on fibronectin. International Journal of Cancer, 52, 594–603.CrossRefPubMedGoogle Scholar
  56. 56.
    Timár, J., Bazaz, R., Kimpler, V., Haddad, M., Tang, D. G., et al. (1995). Immunomorphological characterization and effects of 12-(S)-HETE on a dynamic intracellular pool of the alphaIIb beta3 integrin in melanoma cells. Journal of Cell Science, 108, 2175–2186.PubMedGoogle Scholar
  57. 57.
    Tímár, J., Trikha, M., Szekeres, K., Bazaz, R., & Honn, K. V. (1998). Expression and function of the high affinity alphaIIb beta3 integrin in murine melanoma cells. Clinical & Experimental Metastasis, 16, 437–445.CrossRefGoogle Scholar
  58. 58.
    Liu, B., Khan, W. A., Hannun, Y. A., Tímár, J., Taylor, J. D., et al. (1995). 12(S)-Hydroxyeicosatetraenoic acid and 13(S)-hydroxyoctadecadienoic acid regulation of protein kinase C-alpha in melanoma cells: role of receptor mediated hydrolysis of inositol phospholipids. PNAS, 92, 9323–9327.CrossRefPubMedGoogle Scholar
  59. 59.
    Guo, Y., Zhang, W., Giroux, C., Cai, Y., Ekambaram, P., et al. (2011). Identification of the orphan G protein-coupled receptor GPR31 as a receptor for 12(S)-hydroxyeicosatetraenoic acid. The Journal of Biological Chemistry, 286, 33,832–33,840.CrossRefGoogle Scholar
  60. 60.
    Nguyen, C. H., Stadler, S., Brenner, S., Huttary, N., Krieger, S., et al. 2016, Cancer cell-derived 12(S)-HETE signals via 12-HETE receptor, RHO, ROCK and MLC2 to induce lymph endothelial barrier breaching. British Journal of Cancer, 115, 364–370.Google Scholar
  61. 61.
    Tímár, J., Silletti, S., Bazaz, R., Raz, A., & Honn, K. V. (1993). Regulation of melanoma-cell motility by the lipoxygenase metabolite 12(S)-HETE. International Journal of Cancer, 55, 1003–1010.CrossRefPubMedGoogle Scholar
  62. 62.
    Tímár, J., Trikha, M., Szekeres, K., Bazaz, R., Tóvári, J., et al. (1996). Autocrine motility factor signals integrin-mediated metastatic melanoma cell adhesion and invasion. Cancer Research, 56, 1902–1908.PubMedGoogle Scholar
  63. 63.
    Tímár, J., Sz, T., Tóvári, J., Paku, S., & Raz, A. (1999). Autocrine motility factor (neuroleukin, phosphohexose isomerase) induces cell movement through 12-lipoxygenase-dependent tyrosine phosphorylation and serine dephosphorylation events. Clinical and Experimental Metastasis, 17, 809–816.CrossRefPubMedGoogle Scholar
  64. 64.
    Yeung, J., Apopa, P. L., Vesci, J., Kenyon, V., Rai, G., et al. (2012). Protein kinase C regulation of 12-lipoxygenase-mediated human platelet activation. Molecular Pharmacology, 81, 420–430.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Dilly, A. K., Tang, K., Guo, Y., Joshi, S., Ekambaram, P., et al. (2017). Convergence of eicosanoid and integrin biology: role of SRC in 12-LOX activation. Experimental Cell Research, 351, 1–10.CrossRefPubMedGoogle Scholar
  66. 66.
    Tang, D. G., Li, L., Zhu, Z., Joshi, B., Johnson, C. R., et al. (1998). BMD188: a novel hydroxamic acid compound, demosntrates potent anti-prostate cancer effects in vitro and in vivo by inducing apoptosis: requirements for mitochondria, reactive oxygen species and proteases. Pathology Oncology Research, 4, 179–190.CrossRefPubMedGoogle Scholar
  67. 67.
    Adili, R., Tourdot, B. E., Mast, K., Yeung, J., Freedman, J. C., et al. (2017). First selective 12-LOX inhibitor ML355 impairs thrombus formation and vessel occlusion in vivo with minimal effects on hemostasis. Arteriosclerosis, Thrombosis, and Vascular Biology, 37, 1828–1838.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Tam, J., Hinden, L., Drori, A., Azar, S., & Baraghithy, S. (2018). The therapeutic potential of targeting the pripheral endocannabinoid/CB1 receptor system. European Journal of Internal Medicine, 49, 23–29.CrossRefPubMedGoogle Scholar
  69. 69.
    Mouslech, Z., & Valla, V. (2009). Endocannabinoid system: an overview of its potential in current medical practice. Neuro Endocrinology Letters, 30, 153–179.PubMedGoogle Scholar
  70. 70.
    Liu, J., Wang, L., Harvey-White, J., Huang, B. X., Kim, H. Y., et al. (2008). Multiple pathways involved in the biosynthesis of anadamide. Neuropharmacol, 54, 1–7.CrossRefGoogle Scholar
  71. 71.
    Wang, J., & Ueda, N. (2009). Biology of endocannabinoid synthesis system. Prostaglandins & Other Lipid Mediators, 89, 112–119.CrossRefGoogle Scholar
  72. 72.
    Bifulco, D., & Di Marzo, V. (2002). Targeting the endocannabinoid system in cancer therapy: a call for further research. Nature Medicine, 8, 547–550.CrossRefPubMedGoogle Scholar
  73. 73.
    Schwarz, R., Ramer, R., & Hinz, B. (2018). Targeting the endocannabinoid system as a potential anticancer approach. Drug Metabolism Reviews, 50, 26–53.CrossRefPubMedGoogle Scholar
  74. 74.
    Fonseca, B. M., Teixeira, N. A., & Correia-da-Silva, G. (2017). Cannabinoids as modulators of cell death: clinical applications and future directions. Reviews of Physiology, Biochemistry and Pharmacology, 173, 63–88.CrossRefPubMedGoogle Scholar
  75. 75.
    Carpi, S., Fogli, S., Polini, B., Montagnani, V., Podesta, A., et al. (2017). Tumor-promoting effects of cannabinoid receptor type 1 in human melanoma cells. Toxicology In Vitro, 40, 272–279.CrossRefPubMedGoogle Scholar
  76. 76.
    Magina, S., Esteves-Pinto, C., Moura, E., Serrao, M. P., Moura, D., et al. (2011). Inhibition of basal and ultraviolet B-induced melanogenesis by cannbinoid CB1 receptors: a keratinocyte-dependent effect. Archives of Dermatological Research, 303, 201–210.CrossRefPubMedGoogle Scholar
  77. 77.
    Sailler, S., Schmitz, K., Jager, E., Ferreiros, N., Wicker, S., et al. (2014). Regulation of circulating endocannabinoids associated with cancer and metastases in mice and humans. Oncoscience, 1, 272–282.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Adinolfi, B., Romanini, A., Vanni, A., Martinotti, E., Chicca, A., et al. (2013). Anticancer activity of anandamide in human cutaneous melanoma cells. European Journal of Pharmacology, 718, 154–159.CrossRefPubMedGoogle Scholar
  79. 79.
    Grimaldi, C., Pisanti, S., Laezza, C., Malfitano, A. M., Santoro, A., et al. (2006). Anadamide inhibits adhesion and migration of breast cancer cells. Experimental Cell Research, 312, 363–373.CrossRefPubMedGoogle Scholar
  80. 80.
    Ramer, R., & Hinz, B. (2008). Inhibition of cancer cell invasion by cannabinoids via increased expression of tissue inhibitor of matrix metalloproteinase-1. Journal of the National Cancer Institute, 100, 59–69.CrossRefPubMedGoogle Scholar
  81. 81.
    Madhunapantula, S. V., & Robertson, G. P. (2017). Targeting protein kinase-b3 (akt3) signaling in melanoma. Expert Opinion on Therapeutic Targets, 21, 273–290.CrossRefPubMedGoogle Scholar
  82. 82.
    Deli, T., Varga, N., Ádám, A., Kenessey, I., Rásó, E., et al. (2007). Functional genomics of calcium channels in human melanoma cells. International Journal of Cancer, 121, 55–65.CrossRefPubMedGoogle Scholar
  83. 83.
    Ando, H., Kawaai, K., Bonneau, B., & Mikoshiba, K. (2017). Remodeling of Ca2+ signaling in cancer: regulation of inositol 1,4,5-triphosphate receptors through oncogenes and tumor suppressors. Advances in Biological Regulation, 2018,(68), 64–76.Google Scholar
  84. 84.
    Marom, M., Haklai, R., Ben-Baruch, G., Marciano, D., Egozi, Y., & Kloog, Y. (1995). Selective inhibition of Ras-dependent cell growth by farnesylthiosalisylic acid. The Journal of Biological Chemistry, 270, 22,263–22,270.CrossRefGoogle Scholar
  85. 85.
    Smalley, K. S., & Eisen, T. G. (2003). Farnesyl transferase inhibitor SCH66336 is cytostatic, pro-apoptotic and enhances chemosensitivity to cisplatin in melanoma cells. International Journal of Cancer, 105, 165–175.CrossRefPubMedGoogle Scholar
  86. 86.
    Niessner, H., Beck, D., Sinnberg, T., Lasithiotakis, K., Maczey, E., et al. (2011). The farnesyl transferase inhibitor lonafarnib inhibits mTOR signaling and enforces sorafenib-induced apoptosis in melanoma cells. The Journal of Investigative Dermatology, 131, 468–479.Google Scholar
  87. 87.
    Gajewski, T. F., Niedzwiecki, D., Johnson, J., Linette, G., Bucher, C., et al. (2006). Phase II study of farnezyltransferase inhibitor R115777 in advanced melanoma CALGB500104. Journal of Clinical Oncology S24, abstr8014.Google Scholar
  88. 88.
    Mangoli, K. A., Moon, J., Flaherty, L. E., Lao, C. D., Akerley, W. L., et al. (2012). Randomized phase II trial of sorafenib with temsirolimus or tipifarnib in untreated metastatic melanoma (S0438). Clinical Cancer Research, 18, 1129–1137.CrossRefGoogle Scholar
  89. 89.
    Amin, D., Cornell, S. A., Gustafson, S. K., Needle, S. J., Ullrich, J. W., & E, G. (1992). Bisphosphonates used for the treatment of bone disorders inhibit squalene synthase and cholesterol biosynthesis. Journal of Lipid Research, 33, 1657–1663.PubMedGoogle Scholar
  90. 90.
    van Beek, E., Pieterman, E., Cohen, L., Lowik, C., & Papapoulos, S. (1999). Farnesyl pyrophosphate synthase is the molecular target of nitrogen-containing bisphosphonates. Biochemical and Biophysical Research Communications, 264, 108–111.CrossRefPubMedGoogle Scholar
  91. 91.
    Gnant, M., Mlineritsch, B., Stoeger, H., Luschin-Ebengreuth, G., Knauer, M., et al. (2015). Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12. Annals of Oncology, 26, 313–320.CrossRefPubMedGoogle Scholar
  92. 92.
    Forsea, A. M., Muller, C., Riebeling, C., Orfanos, C. E., & Geilen, C. C. (2004). Nitrogen-containing bisphosphonates inhibit cell cycle progression in human melanoma cells. British Journal of Cancer, 91, 803–810.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Laggner, U., Lopez, J. S., Perera, G., Warbey, V. S., Sita-Lumsden, A., et al. (2009). Regression of melanoma metastases following treatment with the n-bisphosphonate zoledronate and localized radiotherapy. Clinical Immunology, 131, 367–373.CrossRefPubMedGoogle Scholar
  94. 94.
    Tanimori, Y., Tsubaki, M., Yamazoe, Y., Satou, T., Itoh, T., et al. (2010). Nitrogen-containing bisphosphonate, YM529/ONO-5920, inhibits tumor metastasis in mouse melanoma through suppression of the Rho/ROCK pathway. Clinical & Experimental Metastasis, 27, 529–538.CrossRefGoogle Scholar
  95. 95.
    Riebeling, C., Forsea, A. M., Raisova, M., Orfanos, C. E., & Geilen, C. C. (2002). The bisphosphonate pamidronate induces apoptosis in human melanoma cells in vitro. British Journal of Cancer, 87, 366–371.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Shellman, Y. G., Ribble, D., Miller, L., Gendall, J., Vanbuskirk, K., et al. (2005). Lovastatin-induced apoptosis in human melanoma cell lines. Melanoma Research, 15, 83–89.CrossRefPubMedGoogle Scholar
  97. 97.
    Glynn, S. A., O’Sullivan, D., Eustace, A. J., Clynes, M., & O’Donovan, N. (2008). The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, simvastatin, lovastatin and mevastatin inhibit proliferation and invasion of melanoma cells. BMC Cancer, 8, 9.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Saito, A., Saito, N., Mol, W., Furukawa, H., Tsutsumida, A., et al. (2008). Simvastatin inhibits growth via apoptosis and the induction of cell cycle arrest in human melanoma cells. Melanoma Research, 18, 85–94.CrossRefPubMedGoogle Scholar
  99. 99.
    Sarrabayrouse, G., Synaeve, C., Leveque, K., Favre, G., & Tilkin-Mariame, A. F. (2007). Statins stimulate in vitro membrane FasL expression and lymphocyte apoptosis through RhoA/ROCK pathway in murine melanoma cells. Neoplasia, 9, 1078–1090.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Kidera, Y., Tsubaki, M., Yamazoe, Y., Shoji, K., Nakamura, H., et al. (2010). Reduction of lung metastasis, cell invasion, and adhesion in mouse melanoma by statin-induced blockade of the Rho/Rho-associated coiled-coil-containing protein kinase pathway. Journal of Experimental & Clinical Cancer Research, 29, 127.CrossRefGoogle Scholar
  101. 101.
    Tsubaki, M., Takeda, T., Kino, T., Obata, N., Itoh, T., et al. (2015). Statins improve survival by inhibiting spontaneous metastasis and tumor growth in a mouse melanoma model. American Journal of Cancer Research, 5, 3186–3197.PubMedPubMedCentralGoogle Scholar
  102. 102.
    Kretzer, I. F., Maria, D. A., Guido, M. C., Contente, T. C., & Maranhao, R. C. (2016). Simvastatin increases the antineoplastic actions of paclitaxel carried in lipid nanoemulsions in melanoma-bearing mice. International Journal of Nanomedicine, 11, 885–904.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Feleszko, W., Mlynarczuk, I., Olszewska, D., Jalili, A., Grzela, T., et al. (2002). Lovastatin potentiates antitumor activity of doxorubicin in murine melanoma via an apoptosis-dependent mechanism. International Journal of Cancer, 100, 111–118.CrossRefPubMedGoogle Scholar
  104. 104.
    Efimova, E. V., Ricco, N., Labay, E., Mauceri, H. J., Flor, A. C., et al. (2018). HMG-CoA Reductase inhibition delays DNA repair and promotes senescence after tumor irradiation. Molecular Cancer Therapeutics, 17, 407–418.CrossRefPubMedGoogle Scholar
  105. 105.
    Livingstone, E., Hollestein, L. M., Herk-Sukel, M. P. P., Poll-Franse, A., Joosse, B., et al. (2014). Statin use and its effect on all-cause mortality of melanoma patients: a population-based Dutch cohort study. Cancer Medicine, 3, 1284–1293.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    von Schuckmann, L. A., Smith, D., Hughes, M. C. B., Malt, M., van der Pols, J. C., et al. (2017). Associations of statins and diabetes with diagnosis of ulcerated cutaneous melanoma. The Journal of Investigative Dermatology, 137, 2599–2605.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.2nd Department of PathologySemmelweis UniversityBudapestHungary
  2. 2.Molecular Oncology Research GroupSemmelweis UniversityBudapestHungary
  3. 3.Department of Throracic SurgeryUniversity Hospital EssenEssenGermany

Personalised recommendations