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

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.

BIX01294, an inhibitor of histone methyltransferase, induces autophagy-dependent differentiation of glioma stem-like cells

“…Activation of the autophagic process is associated with GSC differentiation1718192044. Using qRT–PCR we found significantly higher levels of ATG5, ATG7, BECN1, ULK1 and LC3B mRNA in L0125 cultures upon serum- and ATRA-induced differentiation (Fig.…”

“…Activation of the autophagic process may promote GSC differentiation and increase radio- and chemosensitivity17181920. Autophagy is a dynamic recycling process associated with the formation of autophagosomes, the cytosolic double-membrane vesicles that engulf cellular components21.…”

Abrus agglutinin stimulates BMP‐2‐dependent differentiation through autophagic degradation of β‐catenin in colon cancer stem cells

“…Activation of autophagy has been described as an essential step for differentiation. For instance, cannabidiol stimulates autophagy to induce differentiation in glioma‐initiating cells . Although the detailed mechanism is required to be investigated, autophagy‐regulatory molecule hVps34 has been identified to interact with AGG‐elicited BMP‐2 to activate autophagy for differentiation in colon CSCs.…”

Selective Estrogen Receptor Modulators: Cannabinoid Receptor Inverse Agonists with Differential CB1 and CB2 Selectivity

“…One ridaifen compound in particular (ridaifen-B) induces autophagy in a human T-cell lymphoma cell line devoid of estrogen receptors (Nagahara et al, 2013), implicating a novel non-ER target for this class of compounds. Importantly, ridaifen compounds exhibit growth-inhibitory effects in many types of cancer that are similarly sensitive to cannabinoids, such as ER-negative breast cancer, gliomas, lung carcinoma, prostate cancer and leukemia/lymphoma (McKallip et al, 2006; Chakravarti et al, 2014; Nabissi et al, 2015). Cannabinoids produce efficacious anti-tumor activity by a variety of mechanisms, including inhibition of proliferation, induction of apoptosis, and inhibition of angiogenesis (Chakravarti et al, 2014).…”