Abstract
Identifying the molecular mechanisms responsible for the resistance of gliomas to anticancer treatments is an issue of great therapeutic interest. Δ9-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.
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Abbreviations
- THC:
-
Δ9-tetrahydrocannabinol
- GBM:
-
glioblastoma multiforme
- ER:
-
endoplasmic reticulum
- TRB3:
-
tribbles homolog 3
- mTORC1:
-
mammalian target of rapamycin complex 1m
- ALK:
-
anaplastic lymphoma kinase receptor
- Mdk:
-
midkine
- PTN:
-
pleiotrophin
- PI3K:
-
phosphatidylinositol 3-kinase
- RPTP:
-
protein-tyrosine phosphatase, receptor-type, zeta-1
- LRP1:
-
low-density lipoprotein receptor-related protein 1
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Acknowledgements
This work was supported by grants from Spanish Ministry of Science and Innovation (MICINN) (PS09/01401; HF2005/0021, FR2009-0052 and IT2009-0053 to GV; SAF2006/00918 to MG), Santander-Complutense (PR34/07-15856 to GV), Comunidad de Madrid (S-SAL/0261/2006 to MG). ML was sequentially the recipient of a ‘Juan de la Cierva’ contract, a postdoctoral contract from Spanish Ministry of Education and Science (MEC) and a postdoctoral contract from Comunidad de Madrid. ST was recipient of a research formation contract from Comunidad de Madrid, MS was recipient of a fellowship from MEC and of a research formation contract from Comunidad de Madrid, AC was recipient of fellowships from Gobierno Vasco, FEBS and EMBO. SH-T has a technician contract from MICINN and Fondo Social Europeo. We thank Horacio Zimman and Carmen Moreno from Hospital Clínico San Carlos as well as Leyre Urigüen from Universidad del Pais Vasco for their kind collaboration in the processing and delivery of glioma samples; Miguel Ángel Piris, Raquel Villuendas, Paloma Cueva and Rosa Pérez for technical advice in the gene expression experiments and other members of our lab for their continuous support.
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Lorente, M., Torres, S., Salazar, M. et al. Stimulation of the midkine/ALK axis renders glioma cells resistant to cannabinoid antitumoral action. Cell Death Differ 18, 959–973 (2011). https://doi.org/10.1038/cdd.2010.170
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DOI: https://doi.org/10.1038/cdd.2010.170
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