title: beta-arrestin2 inhibits opioid-induced breast cancer cell death through Akt and caspase-8 pathways.
abstract: beta-arrestins, a family of regulatory and scaffold proteins, are well-known negative regulators of G-protein-coupled receptors (GPCRs) including opioid receptors. Recent studies have shown that beta-arrestin2 plays a potential role in inhibiting cell death. It has been reported that opioids such as morphine induce cell death at high concentrations (>500 microM for 24 hours), which is similar to morphine plasma concentrations in cancer patients receiving chronic morphine treatment for pain relievers. However, the role of beta-arrestin2 in opioid-induced cell death remains to be elucidated. We report here that beta-arrestin2 significantly blocks morphine-induced number of cell death in human breast cancer MCF-7 and MDA-MB231 cells. Suppression of endogenous beta-arrestin2 by specific RNA interfering (RNAi) and morphine treatment significantly attenuates the levels of phosphorylated Akt compared with inhibition of beta-arrestin2 or morphine treatment alone. However, blockade of morphine-induced cell death by beta-arrestin2 seems to be dependent on the inhibition of caspase-8, as inhibition of beta-arrestin2 and morphine treatment significantly enhanced the levels of cleaved caspase-8. These studies show for the first time that beta-arrestin2 blocks morphine-induced cell death through anti-apoptotic Akt and pro-apoptotic caspase-8 pathways. Therefore, targeting beta-arrestin2 may be useful for treating side effects of opioids as pain relievers for cancer patients.
  
  
  BACKGROUND
  Breast cancer, beta-arrestin, opioid. Akt, caspase-8,cell death.
authors.affiliation: Department of Internal Medicine, James Quillen College of Medicine, East Tennessee State University, TN, USA.
authors.forename: M
authors.initials: M
authors.lastname: Zhao
authors.forename: G
authors.initials: G
authors.lastname: Zhou
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: T
authors.initials: T
authors.lastname: Chen
authors.forename: X
authors.initials: X
authors.lastname: Sun
authors.forename: C
authors.initials: C
authors.lastname: Stuart
authors.forename: G
authors.initials: G
authors.lastname: Hanley
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: D
authors.initials: D
authors.lastname: Yin
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D019390:Arrestins / Q000502:physiology*; D001943:Breast Neoplasms / Q000473:pathology*; D053181:Caspase 8 / Q000502:physiology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D009020:Morphine / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D000071557:beta-Arrestins; D009020:Morphine; D051057:Proto-Oncogene Proteins c-akt; D053181:Caspase 8