Hormonal regulation of β<sub>2</sub>‐adrenergic receptor level in prostate cancer

Ramberg, Håkon; Eide, T. J.; Krobert, Kurt A.; Levy, Finn Olav; Dizeyi, Nishtman; Bjartell, Anders; Abrahamsson, Per‐Anders; Taskén, Kristin Austlid

doi:10.1002/pros.20778

Cited by 40 publications

(46 citation statements)

References 36 publications

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“…Expression of functional ADRB2 was previously reported in normal prostate epithelium and in prostate cancer cells, including LNCaP and C42 human prostate cancer cells and rodent prostates (12,20,45,46). We confirmed expression of ADRB2 in prostate cancer models (Hi-Myc mouse prostates and C42 prostate cancer cells) as well as in human prostates (Supplemental Figure 11).…”

Section: Figuresupporting

confidence: 86%

“…Second, antiapoptotic effects of stress will be restricted to cancer cells that express components of the ADRB2/PKA/BAD pathway. ADRB2, PKA, and BAD are ubiquitously expressed in normal prostate epithelial cells and in prostate cancer cells (20,45,(48)(49)(50). Expression of ADRB2 is regulated by androgen and triiodothyronine and is reportedly increased in malignant prostate glands and in metastatic tumors (45).…”

Section: Figurementioning

confidence: 99%

“…ADRB2, PKA, and BAD are ubiquitously expressed in normal prostate epithelial cells and in prostate cancer cells (20,45,(48)(49)(50). Expression of ADRB2 is regulated by androgen and triiodothyronine and is reportedly increased in malignant prostate glands and in metastatic tumors (45). Yet another publication showed biphasic changes in ADRB2 expression characterized by increased levels of PIN and localized prostate cancer, followed by reduction of ADRB2 in metastatic cancer specimens due to transcriptional suppression by EZH2 (51).…”

Section: Figurementioning

confidence: 99%

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Behavioral stress accelerates prostate cancer development in mice

Hassan

Karpova²,

Daniele³

et al. 2013

J. Clin. Invest.

171

211

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Prostate cancer patients have increased levels of stress and anxiety. Conversely, men who take beta blockers, which interfere with signaling from the stress hormones adrenaline and noradrenaline, have a lower incidence of prostate cancer; however, the mechanisms underlying stress-prostate cancer interactions are unknown. Here, we report that stress promotes prostate carcinogenesis in mice in an adrenaline-dependent manner. Behavioral stress inhibited apoptosis and delayed prostate tumor involution both in phosphatase and tensin homolog-deficient (PTEN-deficient) prostate cancer xenografts treated with PI3K inhibitor and in prostate tumors of mice with prostate-restricted expression of c-MYC (Hi-Myc mice) subjected to androgen ablation therapy with bicalutamide. Additionally, stress accelerated prostate cancer development in Hi-Myc mice. The effects of stress were prevented by treatment with the selective β 2 -adrenergic receptor (ADRB2) antagonist ICI118,551 or by inducible expression of PKA inhibitor (PKI) or of BCL2-associated death promoter (BAD) with a mutated PKA phosphorylation site (BAD S112A ) in xenograft tumors. Effects of stress were also blocked in Hi-Myc mice expressing phosphorylation-deficient BAD (BAD 3SA ). These results demonstrate interactions between prostate tumors and the psychosocial environment mediated by activation of an adrenaline/ADRB2/ PKA/BAD antiapoptotic signaling pathway. Our findings could be used to identify prostate cancer patients who could benefit from stress reduction or from pharmacological inhibition of stress-induced signaling.

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Section: Figuresupporting

confidence: 86%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

See 1 more Smart Citation

Behavioral stress accelerates prostate cancer development in mice

Hassan

Karpova²,

Daniele³

et al. 2013

J. Clin. Invest.

171

211

View full text Add to dashboard Cite

show abstract

“…The animals had free access to rat chow (Purina) and tap water. LNCaP cells (5 × 10 6 ) were subcutaneously malignancy (15). A pilot study in prostate biopsies showed an association between high levels of circulating epinephrine (>1 nmol/L) and phosphorylation of a target of PKA, the cAMP response element binding protein (pCREB) (16).…”

Section: Balb/c Nude Mice and Lncap Tumor Inductionmentioning

confidence: 99%

Triiodothyronine Attenuates Prostate Cancer Progression Mediated by β-Adrenergic Stimulation

Delgado‐González

Sánchez-Tusié

Morales

et al. 2016

Mol Med

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Prostate cancer cells are responsive to adrenergic and thyroid stimuli. It is well established that β-adrenergic activation (protein kinase A [PKA]/cAMP response element binding protein [CREB]) promotes cancer progression, but the role of thyroid hormones is poorly understood. We analyzed the effects of β-adrenergic stimulation (isoproterenol [ISO]) and/or thyroid hormone on neuroendocrine (NE) differentiation and cell invasion, using in vivo (LNCaP tumor) and in vitro models (LNCaP and DU145 human cells). Nude mice were inoculated with LNCaP cells and were treated for 6 wks with ISO (200 μg/d), triiodothyronine (T3, 2.5 μg/d) or both. ISO alone reduced tumor growth but increased tumor expression of cAMP response element (CRE)-dependent genes (real-time polymerase chain reaction, chromogranin A, neuron-specific enolase, survivin, vascular endothelial growth factor [VEGF], urokinase plasmin activator [uPA] and metalloproteinase-9 [MMP-9]) and some proteins related to NE differentiation and/or invasiveness (synaptophysin, VEGF, pCREB). T3 reduced tumor growth and prevented the overexpression of ISO-stimulated factors through a pCREB-independent mechanism. In low invasive LNCaP cells, 50 μmol/L ISO or 100 nmol/L thyroxine (T4) induced the acquisition of NE-like morphology (phase-contrast microscopy), increased VEGF secretion (ELISA) and invasive capacity (Transwell assay), but no synergistic effects were observed after the coadministration of ISO + T4. In contrast, 10 nmol/L T3 alone had no effect, but it prevented the NE-like morphology and invasiveness stimulated by ISO. None of these treatments had any effect on highly invasive DU145 cells. In summary, this study showed that ISO and T4 increase cancer progression, and T3 attenuates ISO-stimulated progression. Further studies are required to determine if changes in the ratio of T4/T3 could be relevant for prostate cancer progression.

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“…MAGI3 also binds to both β 1 and β2AR [31,77]. LNCaP cells show higher expression of β2AR [2,90]. Even MRP4 is highly expressed in prostate cancer [1,11].…”

Section: Summary Of Conclusionmentioning

confidence: 99%

Testing Whether MRP4 (a cAMP Efflux Pump) and the Beta 2 Andrenergic Receptor (an Upstream Regulator of cAMP Signaling Pathways

Potukuchi¹

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Hormonal regulation of β₂‐adrenergic receptor level in prostate cancer

Abstract: The level of beta(2)-AR was increased by T3 in prostatic adenocarcinoma cells and reduced in prostate cancer patients who had received androgen ablation therapy for 3 months.

Cited by 40 publications

References 36 publications

Behavioral stress accelerates prostate cancer development in mice

Behavioral stress accelerates prostate cancer development in mice

Triiodothyronine Attenuates Prostate Cancer Progression Mediated by β-Adrenergic Stimulation

Testing Whether MRP4 (a cAMP Efflux Pump) and the Beta 2 Andrenergic Receptor (an Upstream Regulator of cAMP Signaling Pathways

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Hormonal regulation of β2‐adrenergic receptor level in prostate cancer

Abstract: The level of beta(2)-AR was increased by T3 in prostatic adenocarcinoma cells and reduced in prostate cancer patients who had received androgen ablation therapy for 3 months.

Cited by 40 publications

References 36 publications

Behavioral stress accelerates prostate cancer development in mice

Behavioral stress accelerates prostate cancer development in mice

Triiodothyronine Attenuates Prostate Cancer Progression Mediated by β-Adrenergic Stimulation

Testing Whether MRP4 (a cAMP Efflux Pump) and the Beta 2 Andrenergic Receptor (an Upstream Regulator of cAMP Signaling Pathways

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Hormonal regulation of β₂‐adrenergic receptor level in prostate cancer