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Cannabidiol stimulates A ml‐1a‐dependent glial differentiation and inhibits glioma stem‐like cells proliferation by inducing autophagy in a TRPV 2‐dependent manner
Author(s) -
Nabissi Massimo,
Morelli Maria Beatrice,
Amantini Consuelo,
Liberati Sonia,
Santoni Matteo,
RicciVitiani Lucia,
Pallini Roberto,
Santoni Giorgio
Publication year - 2015
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29573
Subject(s) - cancer research , glioma , trpv , stem cell , cellular differentiation , biology , downregulation and upregulation , pi3k/akt/mtor pathway , protein kinase b , temozolomide , clonogenic assay , microbiology and biotechnology , apoptosis , signal transduction , receptor , biochemistry , gene , transient receptor potential channel , trpv1
Glioma stem‐like cells (GSCs) correspond to a tumor cell subpopulation, involved in glioblastoma multiforme (GBM) tumor initiation and acquired chemoresistance. Currently, drug‐induced differentiation is considered as a promising approach to eradicate this tumor‐driving cell population. Recently, the effect of cannabinoids (CBs) in promoting glial differentiation and inhibiting gliomagenesis has been evidenced. Herein, we demonstrated that cannabidiol (CBD) by activating transient receptor potential vanilloid‐2 (TRPV2) triggers GSCs differentiation activating the autophagic process and inhibits GSCs proliferation and clonogenic capability. Above all, CBD and carmustine (BCNU) in combination overcome the high resistance of GSCs to BCNU treatment, by inducing apoptotic cell death. Acute myeloid leukemia (Aml‐1) transcription factors play a pivotal role in GBM proliferation and differentiation and it is known that Aml‐1 control the expression of several nociceptive receptors. So, we evaluated the expression levels of Aml‐1 spliced variants (Aml‐1a, b and c) in GSCs and during their differentiation. We found that Aml‐1a is upregulated during GSCs differentiation, and its downregulation restores a stem cell phenotype in differentiated GSCs. Since it was demonstrated that CBD induces also TRPV2 expression and that TRPV2 is involved in GSCs differentiation, we evaluated if Aml‐1a interacted directly with TRPV2 promoters. Herein, we found that Aml‐1a binds TRPV2 promoters and that Aml‐1a expression is upregulated by CBD treatment, in a TRPV2 and PI3K/AKT dependent manner. Altogether, these results support a novel mechanism by which CBD inducing TRPV2‐dependent autophagic process stimulates Aml‐1a‐dependent GSCs differentiation, abrogating the BCNU chemoresistance in GSCs.