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Int J Cancer. 2015 Oct 15;137(8):1855-69. doi: 10.1002/ijc.29573. Epub 2015 May 8.

Cannabidiol stimulates Aml-1a-dependent glial differentiation and inhibits glioma stem-like cells proliferation by inducing autophagy in a TRPV2-dependent manner.

Author information

  • 1Section of Experimental Medicine, School of Pharmacy, University of Camerino, Camerino, Italy.
  • 2Department of Molecular Medicine, Sapienza University, Rome, Italy.
  • 3School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy.
  • 4Clinica Di Oncologia Medica, AOU Ospedali Riuniti-Università Politecnica Delle Marche, Ancona, Italy.
  • 5Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore Di Sanità, Rome, Italy.
  • 6Department of Neurosurgery, Università Cattolica Del Sacro Cuore, Rome, Italy.

Abstract

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.

© 2015 UICC.

KEYWORDS:

Aml-1; autophagy; cannabidiol; chemosensitivity; differentiation; glioblastoma stem-like cells

PMID:
25903924
[PubMed - indexed for MEDLINE]
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