Cannabinoid 2 receptor induction by IL-12 and its potential as a therapeutic target for the treatment of anaplastic thyroid carcinoma

Abstract

Anaplastic thyroid carcinoma is the most aggressive type of thyroid malignancies. Previously, we demonstrated that tumorigenicity of anaplastic thyroid carcinoma cell line ARO was significantly reduced following interleukin (IL)-12 gene transfer. We suspected that tumor target structure in ARO/IL-12 cells might be changed and such a change may make them more susceptible to be killed through mechanisms apart from natural killer-dependent pathway. To identify genes involved, we examined gene expression profile of ARO and ARO/IL-12 by microarray analysis of 3757 genes. The most highly expressed gene was cannabinoid receptor 2 (CB2), which was expressed eightfold higher in ARO/IL-12 cells than ARO cells. CB2 agonist JWH133 and mixed CB1/CB2 agonist WIN-55,212-2 could induce significantly higher rate of apoptosis in ARO/IL-12 than ARO cells. Similar results were obtained when ARO cells were transfected with CB2 transgene (ARO/CB2). A considerable regression of thyroid tumors generated by inoculation of ARO/CB2 cells was observed in nude mice following local administration of JWH133. We also demonstrated significant increase in the induction of apoptosis in ARO/IL12 and ARO/CB2 cells following incubation with 15 nM paclitaxel, indicating that tumor cells were sensitized to chemotherapy. These data suggest that CB2 overexpression may contribute to the regression of human anaplastic thyroid tumor in nude mice following IL-12 gene transfer. Given that cannabinoids have shown antitumor effects in many types of cancer models, CB2 may be a viable therapeutic target for the treatment of anaplastic thyroid carcinoma.

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

“…IL-12 gene transfer in to anaplastic thyroid carcinoma cell line (ARO) has anti-tumorigenic effect [122]. This effect was observed due to the activation of cannabinoid receptor.…”

“…This effect was observed due to the activation of cannabinoid receptor. Furthermore they have reported that CB2 agonist JWH-133 and CB1/CB2 agonist WIN-55,212-2 induced apoptosis in ARO and ARO/IL-12 cells [122]. 2-methyl-2'-F-anandamide (Met-F-AEA) also induced apoptosis in thyroid carcinoma cells via activation of p53 and p21 mediated pathway [123].…”

Repositioning therapy for thyroid cancer: new insights on established medications

“…It has also been shown that activation of cannabinoid receptor 2 (CB2) triggers apoptosis in anaplastic TC cell lines. A considerable regression of thyroid tumors generated by inoculation of ARO/CB2 cells was observed in nude mice following administration of CB2 agonist JWH133 (Shi et al 2008). Data indicating that endocannabinoids are effective against cancer cells with activated BRAF/ERK and/or TrkA signaling suggest its potential utility for the treatment of BRAF-positive PTC and TrkA-positive MTC.…”

Cannabinoid receptor ligands as potential anticancer agents — high hopes for new therapies?

“…Moreover, CB 2 receptor activation leads to anticancer effects in other tissues. CB 2 receptor overexpression may contribute to the regression of human anaplastic thyroid tumour in nude mice following interleukin-12 gene transfer, [139] suggesting an inhibitory role of CB 2 in thyroid carcinogenesis. In vitro, Met-F-AEA was shown to reduce thyroid tumour growth [79] and to induce apoptosis in thyroid carcinoma cells.…”