title: Stimulation of the midkine/ALK axis renders glioma cells resistant to cannabinoid antitumoral action.
abstract: Identifying the molecular mechanisms responsible for the resistance of gliomas to anticancer treatments is an issue of great therapeutic interest. Δ(9)-Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoids inhibit tumor growth in animal models of cancer, including glioma, an effect that relies, at least in part, on the stimulation of autophagy-mediated apoptosis in tumor cells. Here, by analyzing the gene expression profile of a large series of human glioma cells with different sensitivity to cannabinoid action, we have identified a subset of genes specifically associated to THC resistance. One of these genes, namely that encoding the growth factor midkine (Mdk), is directly involved in the resistance of glioma cells to cannabinoid treatment. We also show that Mdk mediates its protective effect via the anaplastic lymphoma kinase (ALK) receptor and that Mdk signaling through ALK interferes with cannabinoid-induced autophagic cell death. Furthermore, in vivo Mdk silencing or ALK pharmacological inhibition sensitizes cannabinod-resistant tumors to THC antitumoral action. Altogether, our findings identify Mdk as a pivotal factor involved in the resistance of glioma cells to THC pro-autophagic and antitumoral action, and suggest that selective targeting of the Mdk/ALK axis could help to improve the efficacy of antitumoral therapies for gliomas.
authors.affiliation: Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Lorente
authors.forename: S
authors.initials: S
authors.lastname: Torres
authors.forename: M
authors.initials: M
authors.lastname: Salazar
authors.forename: A
authors.initials: A
authors.lastname: Carracedo
authors.forename: S
authors.initials: S
authors.lastname: Hernández-Tiedra
authors.forename: F
authors.initials: F
authors.lastname: Rodríguez-Fornés
authors.forename: E
authors.initials: E
authors.lastname: García-Taboada
authors.forename: B
authors.initials: B
authors.lastname: Meléndez
authors.forename: M
authors.initials: M
authors.lastname: Mollejo
authors.forename: Y
authors.initials: Y
authors.lastname: Campos-Martín
authors.forename: S A
authors.initials: SA
authors.lastname: Lakatosh
authors.forename: J
authors.initials: J
authors.lastname: Barcia
authors.forename: M
authors.initials: M
authors.lastname: Guzmán
authors.forename: G
authors.initials: G
authors.lastname: Velasco
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002186:Cannabinoids / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D013759:Dronabinol / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000078792:Midkine; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018712:Analgesics, Non-Narcotic; D002186:Cannabinoids; D016207:Cytokines; D009363:Neoplasm Proteins; D000078792:Midkine; D013759:Dronabinol; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases