Inhibitory role of Gi-coupled receptors on cAMP-driven cancers with focus on opioid receptors in lung adenocarcinoma and its stem cells.

The development, progression, metastasis and drug resistance of the most common human cancers are driven by cyclic adenosine monophosphate (cAMP)-signaling downstream of beta-adrenergic receptors (β-Ars) coupled to the stimulatory G-protein G_s. Receptors coupled to the inhibitory G-protein G_i inhibit this signaling cascade by blocking the activation of the enzyme adenylyl cyclase that catalyzes the formation of cAMP and function as the physiological inhibitors of this signaling cascade. Members of the G_i-coupled receptor family widely expressed in the mammalian organism are GABA B receptors (GABA_B-Rs) for the inhibitory neurotransmitter γ-aminobutyric acid (GABA), opioid receptors for endogenous opioid peptides and cannabinoid receptors for endogenous cannabinoids. This review summarizes current evidence for the concept that the activation of G_i-receptor signaling by pharmacological and psychological means is a promising tool for the long-term management of cAMP-driven cancers with special emphasis on the inhibitory effects of opioids on lung adenocarcinoma and its stem cells.