Epinephrine Protects Cancer Cells from Apoptosis via Activation of cAMP-dependent Protein Kinase and BAD Phosphorylation

George Kulik,Adrienne J Smith,Jonathan P Carson,Yelena Karpova,Yong Q Chen,Brian Essau,Konduru S.R Sastry,Avynash Gersappe,Thomas C Register,Sergey Prokopovich,Raymond B Penn,Michael J Weber

doi:10.1074/jbc.m611370200

George Kulik, Adrienne J Smith + Show 10 more

Open Access

https://doi.org/10.1074/jbc.m611370200

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Abstract

The stress hormone epinephrine is known to elicit multiple systemic effects that include changes in cardiovascular parameters and immune responses. However, information about its direct action on cancer cells is limited. Here we provide evidence that epinephrine reduces sensitivity of cancer cells to apoptosis through interaction with beta(2)-adrenergic receptors. The antiapoptotic mechanism of epinephrine primarily involves phosphorylation and inactivation of the proapoptotic protein BAD by cAMP-dependent protein kinase. Moreover, BAD phosphorylation was observed at epinephrine concentrations found after acute and chronic psychosocial stress. Antiapoptotic signaling by epinephrine could be one of the mechanisms by which stress promotes tumorigenesis and decreases the efficacy of anti-cancer therapies.

Highlights

We demonstrate that epinephrine reduces sensitivity of prostate cancer cells to apoptosis via ␤2-AR/protein kinase (PKA) signaling that triggers BAD phosphorylation at S112
We have shown that epinephrine, a catecholamine secreted by adrenal glands and sympathetic nerve terminals in response to stress, protects prostate and breast cancer cells from apoptosis
The antiapoptotic effect of epinephrine is mediated by ␤2 adrenergic receptorand PKA-dependent phosphorylation of BAD at Ser112

Summary

EXPERIMENTAL PROCEDURES

Cell Lines and Transfection—LNCaP and C4-2 cells were a gift from Leland Chung (Emory University, Atlanta, GA). PC3 and MDA-MB-231 cells were obtained from ATCC. LNCaP were maintained in T-medium supplemented with 5% fetal bovine serum, C4-2 and PC3 cells were maintained in RPMI 1640 with 10% fetal bovine serum, and MDA-MB-231 cells were maintained in Dulbecco’s modified Eagle’s medium with 10% fetal bovine serum. All cells were kept in 5% CO2 at 37 °C. Transient transfection was performed at 60–70% confluence using Lipofectamine (Invitrogen) according to the manufacturer’s recommendations

Antiapoptotic Signaling by Epinephrine

RESULTS

Antiapoptotic Effect of Epinephrine Partially Depends on Androgen

Akt phosphorylation remained inhibited in cells treated with

DISCUSSION