학술논문
Non-Canonical Cannabinoid Receptors with Distinct Binding and Signaling Properties in Prostate and Other Cancer Cell Types Mediate Cell Death.
Document Type
Article
Source
Subject
*CANNABINOID receptors
*CANCER cells
*CELL death
*PROSTATE cancer
*MITOCHONDRIAL membranes
*MEMBRANE potential
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Language
ISSN
1661-6596
Abstract
Cannabinoids exert anti-cancer actions; however, the underlying cytotoxic mechanisms and the cannabinoid receptors (CBRs) involved remain unclear. In this study, CBRs were characterized in several cancer cell lines. Radioligand binding screens surprisingly revealed specific binding only for the non-selective cannabinoid [3H]WIN-55,212-2, and not [3H]CP-55,940, indicating that the expressed CBRs exhibit atypical binding properties. Furthermore, [3H]WIN-55,212-2 bound to a single site in all cancer cells with high affinity and varying densities. CBR characteristics were next compared between human prostate cancer cell lines expressing low (PC-3) and high (DU-145) CBR density. Although mRNA for canonical CBRs was detected in both cell lines, only 5 out of 15 compounds with known high affinity for canonical CBRs displaced [3H]WIN-55,212-2 binding. Functional assays further established that CBRs in prostate cancer cells exhibit distinct signaling properties relative to canonical Gi/Go-coupled CBRs. Prostate cancer cells chronically exposed to both CBR agonists and antagonists/inverse agonists produced receptor downregulation, inconsistent with actions at canonical CBRs. Treatment of DU-145 cells with CBR ligands increased LDH-release, decreased ATP-dependent cell viability, and produced mitochondrial membrane potential depolarization. In summary, several cancer cell lines express CBRs with binding and signaling profiles dissimilar to canonical CBRs. Drugs selectively targeting these atypical CBRs might exhibit improved anti-cancer properties. [ABSTRACT FROM AUTHOR]