beta-arrestin2 inhibits opioid-induced breast cancer cell death through Akt and caspase-8 pathways.
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.
Zhao
M
M
Department of Internal Medicine, James Quillen College of Medicine, East Tennessee State University, TN, USA.
Zhou
G
G
Zhang
Y
Y
Chen
T
T
Sun
X
X
Stuart
C
C
Hanley
G
G
Li
J
J
Zhang
J
J
Yin
D
D
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
D019390:Arrestins; D000071557:beta-Arrestins; D009020:Morphine; D051057:Proto-Oncogene Proteins c-akt; D053181:Caspase 8