Cannabinoid Signaling in Glioma Cells

  • Aleksandra Ellert-MiklaszewskaEmail author
  • Iwona A. Ciechomska
  • Bozena Kaminska
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1202)


Cannabinoids are a group of structurally heterogeneous but pharmacologically related compounds, including plant-derived cannabinoids, synthetic substances and endogenous cannabinoids, such as anandamide and 2-arachidonoylglycerol. Cannabinoids elicit a wide range of central and peripheral effects mostly mediated through cannabinoid receptors. There are two types of specific Gi/o-protein-coupled receptors cloned so far, called CB1 and CB2, although an existence of additional cannabinoid-binding receptors has been suggested. CB1 and CB2 differ in their predicted amino acid sequence, tissue distribution, physiological role and signaling mechanisms. Significant alterations of a balance in the cannabinoid system between the levels of endogenous ligands and their receptors occur during malignant transformation in various types of cancer, including gliomas. Cannabinoids exert anti-proliferative action in tumor cells. Induction of cell death by cannabinoid treatment relies on the generation of a pro-apoptotic sphingolipid ceramide and disruption of signaling pathways crucial for regulation of cellular proliferation, differentiation or apoptosis. Increased ceramide levels lead also to ER-stress and autophagy in drug-treated glioblastoma cells. Beyond blocking of tumor cells proliferation cannabinoids inhibit invasiveness, angiogenesis and the stem cell-like properties of glioma cells, showing profound activity in the complex tumor microenvironment. Advances in translational research on cannabinoid signaling led to clinical investigations on the use of cannabinoids in treatments of glioblastomas.


Cannabinoids Apoptosis Autophagy ER-stress Gliomas 








protein kinase B/Akt


activating transcription factor 4


cylic adenosine monophosphate


cannabinoid receptor type 1


cannabinoid receptor type 2




the C/EBP-homologous protein




eukaryotic translation initiation factor 2α


endoplasmic reticulum


extracellular signal-regulated kinase 1/2


fatty acid amide hydrolase


glioma stem-like cells


inositol 1,4,5-trisphosphate




mitogen-activated protein kinase


MAP kinase-ERK kinase


monoacylglycerol lipase


mammalian target of rapamycin, complex 1




phosphatidylinositol 3-kinase


phosphatidylinositol 4,5-bisphosphate


protein kinase A


protein kinase C


phospholipase C


pseudo-kinase tribbles homologue 3


transient receptor potential cation channel subfamily V member 1, capsaicin or vanilloid receptor


synthetic cannabinoid




  1. Aguado T, Carracedo A, Julien B, Velasco G, Milman G, Mechoulam R et al (2007) Cannabinoids induce glioma stem-like cell differentiation and inhibit gliomagenesis. J Biol Chem 282:6854–6862. CrossRefPubMedGoogle Scholar
  2. Andradas C, Caffarel MM, Perez-Gomez E, Salazar M, Lorente M, Velasco G et al (2011) The orphan G protein-coupled receptor GPR55 promotes cancer cell proliferation via ERK. Oncogene 30:245–252. CrossRefPubMedGoogle Scholar
  3. Blazquez C, Casanova ML, Planas A, Gomez Del Pulgar T, Villanueva C, Fernandez-Acenero MJ et al (2003) Inhibition of tumor angiogenesis by cannabinoids. FASEB J 17:529–531. CrossRefPubMedGoogle Scholar
  4. Blazquez C, Gonzalez-Feria L, Alvarez L, Haro A, Casanova ML, Guzman M (2004) Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas. Cancer Res 64:5617–5623. CrossRefPubMedGoogle Scholar
  5. Blazquez C, Carracedo A, Salazar M, Lorente M, Egia A, Gonzalez-Feria L et al (2008a) Down-regulation of tissue inhibitor of metalloproteinases-1 in gliomas: a new marker of cannabinoid antitumoral activity? Neuropharmacology 54:235–243. CrossRefPubMedGoogle Scholar
  6. Blazquez C, Salazar M, Carracedo A, Lorente M, Egia A, Gonzalez-Feria L et al (2008b) Cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression. Cancer Res 68:1945–1952. CrossRefPubMedGoogle Scholar
  7. Caffarel MM, Sarrio D, Palacios J, Guzman M, Sanchez C (2006) Delta9-tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation. Cancer Res 66:6615–6621. CrossRefPubMedGoogle Scholar
  8. Carracedo A, Gironella M, Lorente M, Garcia S, Guzman M, Velasco G et al (2006a) Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Res 66:6748–6755. CrossRefPubMedGoogle Scholar
  9. Carracedo A, Lorente M, Egia A, Blazquez C, Garcia S, Giroux V et al (2006b) The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells. Cancer Cell 9:301–312. CrossRefPubMedGoogle Scholar
  10. Cheng L, Wu Q, Guryanova OA, Huang Z, Huang Q, Rich JN et al (2011) Elevated invasive potential of glioblastoma stem cells. Biochem Biophys Res Commun 406:643–648. CrossRefPubMedPubMedCentralGoogle Scholar
  11. De Jesus ML, Hostalot C, Garibi JM, Salles J, Meana JJ, Callado LF (2010) Opposite changes in cannabinoid CB1 and CB2 receptor expression in human gliomas. Neurochem Int 56:829–833. CrossRefPubMedGoogle Scholar
  12. Dumitru CA, Sandalcioglu IE, Karsak M (2018) Cannabinoids in glioblastoma therapy: new applications for old drugs. Front Mol Neurosci 11(159).
  13. Duntsch C, Divi MK, Jones T, Zhou Q, Krishnamurthy M, Boehm P et al (2006) Safety and efficacy of a novel cannabinoid chemotherapeutic, KM-233, for the treatment of high-grade glioma. J Neuro-Oncol 77:143–152. CrossRefGoogle Scholar
  14. Ellert-Miklaszewska A, Kaminska B, Konarska L (2005) Cannabinoids down-regulate PI3K/Akt and Erk signalling pathways and activate proapoptotic function of bad protein. Cell Signal 17:25–37. CrossRefPubMedGoogle Scholar
  15. Ellert-Miklaszewska A, Grajkowska W, Gabrusiewicz K, Kaminska B, Konarska L (2007) Distinctive pattern of cannabinoid receptor type II (CB2) expression in adult and pediatric brain tumors. Brain Res 1137:161–169. CrossRefPubMedGoogle Scholar
  16. Galve-Roperh I, Sanchez C, Cortes ML, Gomez del Pulgar T, Izquierdo M, Guzman M (2000) Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat Med 6:313–319. CrossRefPubMedGoogle Scholar
  17. Gomez del Pulgar T, Velasco G, Sanchez C, Haro A, Guzman M (2002) De novo-synthesized ceramide is involved in cannabinoid-induced apoptosis. Biochem J 363:183–188. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Gomez O, Arevalo-Martin A, Garcia-Ovejero D, Ortega-Gutierrez S, Cisneros JA, Almazan G et al (2010) The constitutive production of the endocannabinoid 2-arachidonoylglycerol participates in oligodendrocyte differentiation. Glia 58:1913–1927. CrossRefPubMedGoogle Scholar
  19. Gong JP, Onaivi ES, Ishiguro H, Liu QR, Tagliaferro PA, Brusco A et al (2006) Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res 1071:10–23. CrossRefPubMedGoogle Scholar
  20. Guzman M (2003) Cannabinoids: potential anticancer agents. Nat Rev Cancer 3:745–755. CrossRefPubMedGoogle Scholar
  21. Guzman M, Sanchez C, Galve-Roperh I (2001) Control of the cell survival/death decision by cannabinoids. J Mol Med (Berl) 78:613–625CrossRefGoogle Scholar
  22. Held-Feindt J, Dorner L, Sahan G, Mehdorn HM, Mentlein R (2006) Cannabinoid receptors in human astroglial tumors. J Neurochem 98:886–893CrossRefGoogle Scholar
  23. Hermanson DJ, Gamble-George JC, Marnett LJ, Patel S (2014) Substrate-selective COX-2 inhibition as a novel strategy for therapeutic endocannabinoid augmentation. Trends Pharmacol Sci 35:358–367. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Hernandez-Tiedra S, Fabrias G, Davila D, Salanueva IJ, Casas J, Montes LR et al (2016) Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization. Autophagy 12:2213–2229. CrossRefPubMedPubMedCentralGoogle Scholar
  25. Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA et al (2002) International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 54:161–202CrossRefGoogle Scholar
  26. Izzo AA, Aviello G, Petrosino S, Orlando P, Marsicano G, Lutz B et al (2008) Increased endocannabinoid levels reduce the development of precancerous lesions in the mouse colon. J Mol Med (Berl) 86:89–98. CrossRefGoogle Scholar
  27. Kapoor GS, O’Rourke DM (2003) Receptor tyrosine kinase signaling in gliomagenesis: pathobiology and therapeutic approaches. Cancer Biol Ther 2:330–342. CrossRefPubMedGoogle Scholar
  28. Klionsky DJ, Emr SD (2000) Autophagy as a regulated pathway of cellular degradation. Science 290:1717–1721. CrossRefPubMedPubMedCentralGoogle Scholar
  29. Ladin DA, Soliman E, Griffin L, Van Dross R (2016) Preclinical and clinical assessment of cannabinoids as anti-Cancer agents. Front Pharmacol 7(361).
  30. Li Q, Barres BA (2018) Microglia and macrophages in brain homeostasis and disease. Nat Rev Immunol 18:225–242. CrossRefPubMedPubMedCentralGoogle Scholar
  31. Lopez-Valero I, Saiz-Ladera C, Torres S, Hernandez-Tiedra S, Garcia-Taboada E, Rodriguez-Fornes F et al (2018) Targeting glioma initiating cells with a combined therapy of cannabinoids and temozolomide. Biochem Pharmacol 157:266–274. CrossRefPubMedGoogle Scholar
  32. Lu HC, Mackie K (2016) An introduction to the endogenous cannabinoid system. Biol Psychiatry 79:516–525. CrossRefPubMedGoogle Scholar
  33. Maccarrone M, Lorenzon T, Bari M, Melino G, Finazzi-Agro A (2000) Anandamide induces apoptosis in human cells via vanilloid receptors. Evidence for a protective role of cannabinoid receptors J Biol Chem 275:31938–31945. CrossRefPubMedGoogle Scholar
  34. Mackie K (2006) Cannabinoid receptors as therapeutic targets. Annu Rev Pharmacol Toxicol 46:101–122. CrossRefPubMedGoogle Scholar
  35. Mackie K, Stella N (2006) Cannabinoid receptors and endocannabinoids: evidence for new players. AAPS J 8:E298–E306. CrossRefPubMedPubMedCentralGoogle Scholar
  36. Massi P, Vaccani A, Ceruti S, Colombo A, Abbracchio MP, Parolaro D (2004) Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines. J Pharmacol Exp Ther 308:838–845. CrossRefPubMedGoogle Scholar
  37. Massi P, Vaccani A, Bianchessi S, Costa B, Macchi P, Parolaro D (2006) The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells. Cell Mol Life Sci 63:2057–2066. CrossRefPubMedGoogle Scholar
  38. McAllister SD, Chan C, Taft RJ, Luu T, Abood ME, Moore DH et al (2005) Cannabinoids selectively inhibit proliferation and induce death of cultured human glioblastoma multiforme cells. J Neuro-Oncol 74:31–40. CrossRefGoogle Scholar
  39. Mecha M, Feliu A, Carrillo-Salinas FJ, Rueda-Zubiaurre A, Ortega-Gutierrez S, de Sola RG et al (2015) Endocannabinoids drive the acquisition of an alternative phenotype in microglia. Brain Behav Immun 49:233–245. CrossRefPubMedGoogle Scholar
  40. Molina-Holgado E, Vela JM, Arevalo-Martin A, Almazan G, Molina-Holgado F, Borrell J et al (2002) Cannabinoids promote oligodendrocyte progenitor survival: involvement of cannabinoid receptors and phosphatidylinositol-3 kinase/Akt signaling. J Neurosci 22:9742–9753CrossRefGoogle Scholar
  41. Moreno E, Andradas C, Medrano M, Caffarel MM, Perez-Gomez E, Blasco-Benito S et al (2014) Targeting CB2-GPR55 receptor heteromers modulates cancer cell signaling. J Biol Chem 289:21960–21972. CrossRefPubMedPubMedCentralGoogle Scholar
  42. Nabissi M, Morelli MB, Amantini C, Liberati S, Santoni M, Ricci-Vitiani L et al (2015) Cannabidiol stimulates Aml-1a-dependent glial differentiation and inhibits glioma stem-like cells proliferation by inducing autophagy in a TRPV2-dependent manner. Int J Cancer 137:1855–1869. CrossRefPubMedGoogle Scholar
  43. Pazos MR, Nunez E, Benito C, Tolon RM, Romero J (2005) Functional neuroanatomy of the endocannabinoid system. Pharmacol Biochem Behav 81:239–247. CrossRefPubMedGoogle Scholar
  44. Petersen G, Moesgaard B, Schmid PC, Schmid HH, Broholm H, Kosteljanetz M et al (2005) Endocannabinoid metabolism in human glioblastomas and meningiomas compared to human non-tumour brain tissue. J Neurochem 93:299–309CrossRefGoogle Scholar
  45. Pisanti S, Borselli C, Oliviero O, Laezza C, Gazzerro P, Bifulco M (2007) Antiangiogenic activity of the endocannabinoid anandamide: correlation to its tumor-suppressor efficacy. J Cell Physiol 211:495–503. CrossRefPubMedGoogle Scholar
  46. Salazar M, Carracedo A, Salanueva IJ, Hernandez-Tiedra S, Lorente M, Egia A et al (2009) Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J Clin Invest 119:1359–1372. CrossRefPubMedPubMedCentralGoogle Scholar
  47. Sanchez C, Velasco G, Guzman M (1997) Delta9-tetrahydrocannabinol stimulates glucose utilization in C6 glioma cells. Brain Res 767:64–71. CrossRefPubMedGoogle Scholar
  48. Sanchez C, Galve-Roperh I, Canova C, Brachet P, Guzman M (1998) Delta9-tetrahydrocannabinol induces apoptosis in C6 glioma cells. FEBS Lett 436:6–10. CrossRefPubMedGoogle Scholar
  49. Sanchez C, de Ceballos ML, Gomez del Pulgar T, Rueda D, Corbacho C, Velasco G et al (2001) Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res 61:5784–5789PubMedGoogle Scholar
  50. Sarfaraz S, Afaq F, Adhami VM, Mukhtar H (2005) Cannabinoid receptor as a novel target for the treatment of prostate cancer. Cancer Res 65:1635–1641. CrossRefPubMedGoogle Scholar
  51. Schley M, Stander S, Kerner J, Vajkoczy P, Schupfer G, Dusch M et al (2009) Predominant CB2 receptor expression in endothelial cells of glioblastoma in humans. Brain Res Bull 79:333–337. CrossRefPubMedGoogle Scholar
  52. Schroder M, Kaufman RJ (2005) The mammalian unfolded protein response. Annu Rev Biochem 74:739–789. CrossRefPubMedGoogle Scholar
  53. Scott KA, Dalgleish AG, Liu WM (2014) The combination of cannabidiol and Delta9-tetrahydrocannabinol enhances the anticancer effects of radiation in an orthotopic murine glioma model. Mol Cancer Ther 13:2955–2967. CrossRefPubMedGoogle Scholar
  54. Scott KA, Dennis JL, Dalgleish AG, Liu WM (2015) Inhibiting heat shock proteins can potentiate the cytotoxic effect of Cannabidiol in human glioma cells. Anticancer Res 35:5827–5837PubMedGoogle Scholar
  55. Singer E, Judkins J, Salomonis N, Matlaf L, Soteropoulos P, McAllister S et al (2015) Reactive oxygen species-mediated therapeutic response and resistance in glioblastoma. Cell Death Dis 6:e1601. CrossRefPubMedPubMedCentralGoogle Scholar
  56. Solinas M, Massi P, Cantelmo AR, Cattaneo MG, Cammarota R, Bartolini D et al (2012) Cannabidiol inhibits angiogenesis by multiple mechanisms. Br J Pharmacol 167:1218–1231. CrossRefPubMedPubMedCentralGoogle Scholar
  57. Solinas M, Massi P, Cinquina V, Valenti M, Bolognini D, Gariboldi M et al (2013) Cannabidiol, a non-psychoactive cannabinoid compound, inhibits proliferation and invasion in U87-MG and T98G glioma cells through a multitarget effect. PLoS One 8:e76918. CrossRefPubMedPubMedCentralGoogle Scholar
  58. Soroceanu L, Murase R, Limbad C, Singer E, Allison J, Adrados I et al (2013) Id-1 is a key transcriptional regulator of glioblastoma aggressiveness and a novel therapeutic target. Cancer Res 73:1559–1569. CrossRefPubMedGoogle Scholar
  59. Sredni ST, Huang CC, Suzuki M, Pundy T, Chou P, Tomita T (2016) Spontaneous involution of pediatric low-grade gliomas: high expression of cannabinoid receptor 1 (CNR1) at the time of diagnosis may indicate involvement of the endocannabinoid system. Childs Nerv Syst 32:2061–2067. CrossRefPubMedGoogle Scholar
  60. Stella N (2004) Cannabinoid signaling in glial cells. Glia 48:267–277. CrossRefPubMedGoogle Scholar
  61. Stella N (2009) Endocannabinoid signaling in microglial cells. Neuropharmacology 56(Suppl 1):244–253. CrossRefPubMedGoogle Scholar
  62. Stock K, Kumar J, Synowitz M, Petrosino S, Imperatore R, Smith ES et al (2012) Neural precursor cells induce cell death of high-grade astrocytomas through stimulation of TRPV1. Nat Med 18:1232–1238. CrossRefPubMedPubMedCentralGoogle Scholar
  63. Torres S, Lorente M, Rodriguez-Fornes F, Hernandez-Tiedra S, Salazar M, Garcia-Taboada E et al (2011) A combined preclinical therapy of cannabinoids and temozolomide against glioma. Mol Cancer Ther 10:90–103. CrossRefPubMedGoogle Scholar
  64. Vaccani A, Massi P, Colombo A, Rubino T, Parolaro D (2005) Cannabidiol inhibits human glioma cell migration through a cannabinoid receptor-independent mechanism. Br J Pharmacol 144:1032–1036. CrossRefPubMedPubMedCentralGoogle Scholar
  65. Valenzano KJ, Tafesse L, Lee G, Harrison JE, Boulet JM, Gottshall SL et al (2005) Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology 48:658–672. CrossRefPubMedGoogle Scholar
  66. Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K et al (2005) Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310:329–332. CrossRefPubMedGoogle Scholar
  67. Velasco G, Carracedo A, Blazquez C, Lorente M, Aguado T, Haro A et al (2007) Cannabinoids and gliomas. Mol Neurobiol 36:60–67. CrossRefPubMedGoogle Scholar
  68. Wu X, Han L, Zhang X, Li L, Jiang C, Qiu Y et al (2012) Alteration of endocannabinoid system in human gliomas. J Neurochem 120:842–849. CrossRefPubMedGoogle Scholar
  69. Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 87:619–628. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Aleksandra Ellert-Miklaszewska
    • 1
    Email author
  • Iwona A. Ciechomska
    • 1
  • Bozena Kaminska
    • 1
  1. 1.Laboratory of Molecular Neurobiology, Neurobiology Center, Nencki Institute of Experimental BiologyPolish Academy of SciencesWarsawPoland

Personalised recommendations