β2-adrenoreceptor Signaling Increases Therapy Resistance in Prostate Cancer by Upregulating MCL1

Area of Science:

• Oncology
• Molecular Biology
• Endocrinology

Background:

• Psychosocial stress activates the sympathetic nervous system, impacting cancer progression.
• Beta-2 adrenergic receptor (ADRB2) signaling is implicated in therapy resistance and tumor growth.
• Mechanisms of stress-induced cancer progression vary by tumor type.

Purpose of the Study:

• To investigate the role of ADRB2 signaling in mediating stress-induced therapy resistance in prostate cancer.
• To elucidate the molecular pathway linking stress, ADRB2 activation, and apoptosis regulation in prostate cancer cells.
• To explore the clinical relevance of ADRB2/MCL1 pathway in human prostate cancer.

Main Methods:

• Utilized immobilization stress to activate ADRB2 in prostate cancer cells and xenografts.
• Assessed the impact of epinephrine on MCL1 protein expression and apoptosis.
• Investigated the role of protein kinase A (PKA) and androgen receptor (AR) signaling.
• Correlated epinephrine levels and MCL1 expression in human prostate cancer biopsies.

Main Results:

• Epinephrine, elevated during stress, delayed cytotoxic drug-induced MCL1 protein loss in prostate cancer cells.
• This resulted in increased resistance of prostate cancer xenografts to cytotoxic therapies.
• The epinephrine effect on MCL1 was dependent on PKA activity but independent of AR.
• Elevated blood epinephrine levels correlated with increased MCL1 expression in human prostate biopsies.

Conclusions:

• Stress activates an androgen-independent antiapoptotic signaling pathway (ADRB2/PKA/MCL1) in prostate cancer.
• This pathway contributes to therapy resistance in prostate cancer.
• ADRB2 blockers and MCL1 as a biomarker warrant clinical investigation for prostate cancer treatment.