The role of lipid signaling in the progression of malignant melanoma


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.

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Fig. 1
Fig. 2
Fig. 3
Fig. 4



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


  1. 1.

    Timar, J., Vizkeleti, L., Doma, V., Barbai, T., & Rásó, E. (2016). Genetic progression of malignant melanoma. Cancer Metastasis Reviews, 35, 93–107.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  Google 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.

    Article  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  PubMed Central  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  Google 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.

    Article  PubMed  CAS  Google 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.

    CAS  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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  CAS  Google 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.

    Article  Google 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.

    Article  PubMed  CAS  Google 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.

    CAS  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.

    Article  PubMed  PubMed Central  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  PubMed Central  CAS  Google 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.

    Article  PubMed  PubMed Central  CAS  Google 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.

    Article  PubMed  PubMed Central  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  PubMed Central  CAS  Google 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.

  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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  PubMed Central  CAS  Google 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.

    Article  CAS  Google 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.

    Article  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  Google 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.

  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.

    Article  PubMed  CAS  Google 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.

    Article  CAS  Google 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.

  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.

    Article  PubMed  PubMed Central  CAS  Google 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.

    Article  PubMed  PubMed Central  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  PubMed Central  CAS  Google 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.

  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.

    Article  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  Google 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.

    PubMed  CAS  Google 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.

    Article  PubMed  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  PubMed Central  Google 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.

    Article  PubMed  CAS  Google 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.

    PubMed  Google 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.

    Article  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  CAS  Google 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.

  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.

    Article  PubMed  Google 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.

    PubMed  Google 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.

    Article  PubMed  Google 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.

    Article  PubMed  PubMed Central  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  CAS  PubMed Central  Google 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.

    Article  PubMed  CAS  Google 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.

    PubMed  CAS  Google 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.

    Article  CAS  Google Scholar 

  71. 71.

    Wang, J., & Ueda, N. (2009). Biology of endocannabinoid synthesis system. Prostaglandins & Other Lipid Mediators, 89, 112–119.

    Article  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  PubMed Central  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

  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.

    Article  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

  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.

  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.

    Article  Google 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.

    PubMed  CAS  Google 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.

    Article  PubMed  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  PubMed Central  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  CAS  Google 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.

    Article  PubMed  PubMed Central  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  PubMed Central  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  PubMed Central  CAS  Google 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.

    Article  CAS  Google 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.

    PubMed  PubMed Central  CAS  Google 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.

    PubMed  PubMed Central  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  PubMed  PubMed Central  CAS  Google 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.

    Article  CAS  Google Scholar 

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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).

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Correspondence to József Tímár.

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Tímár, J., Hegedüs, B. & Rásó, E. The role of lipid signaling in the progression of malignant melanoma. Cancer Metastasis Rev 37, 245–255 (2018).

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  • Eicosanoid
  • Signaling
  • Melanoma
  • Cyclooxygenase
  • Lipoxygenase
  • Phosphodiestherase-2