β2-AR-HIF-1α: A Novel Regulatory Axis for Stress-Induced Pancreatic Tumor Growth and Angiogenesis

Abstract

The purpose of this study was to test the hypothesis that chronic stress in a negative social and psychological state plays a critical role in pancreatic cancer development and progression. In this study, we created a new stress model system to determine the effects of chronic stress on pancreatic cancer progression. Here, we show that chronic stress not only causes depression in mice, most likely attributed to an elevated level of epinephrine, but also induces pancreatic cancer progression. We provide evidence that the pancreatic cancer progression induced by chronic stress could be blocked to a significant degree by β2-AR inhibitor ICI118 551 or HIF-1α inhibitor 2-methoxyestradiol. Moreover, establishment of pancreatic cancer in mice exposed to chronic stress was accompanied by up-regulation of the expression of MMP-2, MMP-9, and VEGF, mediated by a HIF-1α-dependent β-AR signaling pathway. Our data suggest that the β2-AR-HIF-1α axis regulates stress-induced pancreatic tumor growth and angiogenesis. This study may have a therapeutic or preventive potential for the patients with pancreatic cancer who are especially prone to psychosocial stress challenges.

Repurposing Drugs in Oncology (ReDO)—Propranolol as an anti-cancer agent

“…Furthermore PRO pre-treatment abrogated the effect of adrenergic signalling on HIF-1α, VEGF and angiogenesis. Similar results, using a beta2-adrenergic receptor antagonist (ICI118 551), have been shown in vitro and in vivo in a murine pancreatic cancer model [133]. …”

Recent Advances on the Role of G Protein-Coupled Receptors in Hypoxia-Mediated Signaling

“…Recently, the adrenergic system has been shown to boost tumor angiogenesis and aggressive features through the upregulation of diverse angiogenic factors like VEGF, IL-6, IL-8, matrix metalloproteinase (MMP)-2, and MMP-9 (66,67). The involvement of HIF-1α in the aforementioned biological responses to catecholamine-mediated stress was also evidenced in other studies showing that the β2-adrenergic receptor (AR)/HIF-1α axis regulates angiogenesis and stress-induced pancreatic tumor growth in mouse models (68). In hypoxic melanoma cells, β3-ARs have been found to be upregulated and involved in the increase of VEGF, as evidenced by using two β3-AR blockers (69).…”

Hypoxia inducible factor (HIF)-1α directly activates leptin receptor (Ob-R) in pancreatic cancer cells

“…As a result of hypoxia and genetic mutations, hypoxia inducible factor-1 (HIF-1) is highly expressed in pancreatic cancer cells [13,14], which is predominant in regulating hypoxia-related genes in pancreatic cancer. The transcription factor, HIF-1, is a hetero-dimer, which includes an α subunit and a β subunit [15,16]. In contrast to HIF-1β, HIF-1α subunit, which determines HIF-1 activity, is a predominant mediator in the homeostatic response to hypoxia and stimulation of growth factor.…”

“…Under normoxia, the half-life of HIF-1α is less than 1 minute, degraded through the ubiquitin-proteasome pathway [17]. While hypoxia increased expression of HIF-1α, through reducing ubiquitination or mutation blocking ubiquitination, HIF-1α and HIF-1β quickly polymerizes, forming a dimer dynamic, and thereby regulating the expression of downstream genes [15]. This active transcription factor can recognize and bind to the hypoxiaresponse elements (HREs: 5'-A/GCGTG-3'), and then HIF-1 activates the transcription of its target genes which allows the tumor to adapt to hypoxia [18].…”