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. D 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 autophagymediated 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.

Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy

“…11,12 It has been described that D 9 -tetrahydrocannabinol (D 9 -THC), the main active constituent of marijuana, triggers human glioma cell death through stimulation of an ER stress pathway that activates autophagy and promotes apoptosis. 13,14 Autophagy is a cellular self-digestive process These authors contributed equally to this work. …”

“…11,12 It has been described that D 9 -tetrahydrocannabinol (D 9 -THC), the main active constituent of marijuana, triggers human glioma cell death through stimulation of an ER stress pathway that activates autophagy and promotes apoptosis. 13,14 Autophagy is a cellular self-digestive process whereby bulk cytoplasmic components and intracellular organelles are sequestered into double-membrane vesicles named autophagosomes and delivered for degradation to the lysosomes. 8,15,16 In the liver, autophagy may have an important role in the regulation of energy balance for basic cell functions.…”

Programming of neural cells by (endo)cannabinoids: from physiological rules to emerging therapies

“…The molecular basis of this ‘yin-yang’ behavior is incompletely understood. Nevertheless, the possibility that it relies on different patterns of CB 1 R/CB 2 R expression and/or pre-coupling to effectors seems unlikely for a number of reasons: glioma cell lines resistant to cannabinoid-induced apoptosis express similar amounts of CB 1 R and/or CB 2 R compared with cannabinoid-sensitive lines, and pharmacological studies using cannabinoid receptor subtype-selective antagonists support that either CB 1 R or CB 2 R can signal apoptosis in cannabinoid-sensitive glioma cells 183,184 . In addition, the short-term (minute-range) coupling of CB 1 R/CB 2 R to key cell signaling pathways such as Erk and Akt is similar in glioma cell lines that are sensitive or resistant to cannabinoid-induced apoptosis 183,185 , as well as in primary astroglia 125 or oligodendroglia 121 .…”

Cannabinoids as therapeutic agents in cancer: current status and future implications

“…At 12mg/kg daily dose of KM-233 for 20 days revealed around 80% reduction in tumor size in the orthotopic model of U87MG [109]. Glioma cells develop resistance to cannabinoid treatment due to the upregulation of Amphiregulin (EGFR family ligand) and the growth factor midkine (Mdk) [110-111]. Amphiregulin expression was associated with increased ERK activation and Mdk mediated its protective effect through ALK which interferes with autophagic cell death [112].…”