Cancer cells ability to evade apoptos-stress
A study published in the Journal of Clinical Investigation indicates that stress or the stress hormone adrenaline, through stimulation of beta-adrenoreceptors (ADRs), activate signaling pathways that lead to the inhibition of apoptosis. This enables prostate cancer cells to evade apoptosis, which is an important feature of tumor growth and metastasis.
An increasing body of evidence indicates that psychological stress, i.e., stress hormones and mediators, are involved in the development and progression of cancer – affecting directly or indirectly tumor growth, angiogenesis, and migration or invasion of tumor cells.
The idea that psychological factors may contribute to cancer development and progression is not new. It was probably Galen who first integrated the ‘immune system’ or ‘cancer’ with the person’s emotional and physiologic processes – circa 200 A.D. he wrote that melancholic women were more prone to develop ‘swellings’ of the breasts than were sanguine women.
In 1701, the English physician Gendron emphasized the effects of “disasters of life as occasion much trouble and grief” in the causation of cancer. In fact, throughout 18th and 19th century physicians had a firm belief that ‘stressful states’ predisposed to cancer.
Generally, research and clinical data, mostly from the last 10-15 years, strongly indicate that the sympathetic nervous system (SNS) innervation and a hyperactive SNS via activation of the β2-adrenergic receptors (β2-ARs) contributes to tumor-related immunosuppression and by extension to tumor proliferation, growth and metastasis.
Sympathetic signaling, often associated with obesity and chronic stress, is increasingly acknowledged as a contributor to cancer aggressiveness. In prostate cancer, intact sympathetic nerves are critical for tumor formation, which, when suppressed, induce apoptosis and blocks tumor growth.
In a 2013 study published in Science magazine, Claire Magnon et al. showed that autonomic nerves contribute to prostate cancer development, where the sympathetic nervous system (SNS) via the activation of β2 and β3-adrenergic receptor pathway participate in the early phase of tumor development. Moreover, a study with a cohort of 3561 prostate cancer patients indicated that the use of β-blockers was associated with reduced prostate cancer-specific mortality in patients with high-risk or metastatic disease.
The ability of tumor cells to evade apoptosis (the process of programmed cell death) is a characteristic hallmark of cancer. To date, there is no definitive experimental evidence on the mechanisms by which behavioral stress may influence prostate cancer development and therapy resistance.
In the Journal of Clinical Investigation study, Sazzad Hassan and colleagues from the Wake Forest University School of Medicine, Winston-Salem, North Carolina demonstrated that in 2 mouse models of prostate cancer – a prostate specific, androgen-dependent transgenic model, and an androgen-independent xenograft model – stress activated the ADRB2/PKA/BAD anti-apoptotic signaling pathway.
Thus, stress may represent a newly defined environmental factor contributing to prostate cancer pathogenesis through an anti-apoptotic signaling pathway that impinges on BCL2-associated death promoter (BAD) phosphorylation. These results are probably the first to establish the critical role of BAD phosphorylation in stress- or adrenaline-induced anti-apoptotic signaling in prostate tumors in vivo.
Importantly, the authors also demonstrate that stress may lead to resistance to anti-androgen (bicalutamide) therapy, an effect they were able to prevent by treatment with an ADRB2 antagonist (a ‘beta-blocker’).
According to the authors, as the prostate cancer diagnosis often increases stress and anxiety levels, the activation of a stress-induced anti-apoptotic pathway may lead to a vicious cycle of stress and cancer progression. The authors also expect that their results could help the identification of biomarkers to predict how a given tumor will respond to stress, and/or distinguish patients’ subgroups that could benefit from stress reduction and pharmacological blockade of stress-induced signaling.
In summary, in 2 distinct in vivo models of prostate cancer, the study indicates that behavioral stress activated the adrenaline/ADRB2/PKA/BAD antiapoptotic signaling pathway, which in turn reduced therapeutic sensitivity and accelerated prostate cancer development. These data introduce behavioral stress as a new environmental component contributing to prostate cancer pathogenesis through a defined antiapoptotic signaling pathway that impinges on BAD phosphorylation.
Comments on this study, by a group of experts working on similar issues, are available in the same issue of the Journal of Clinical Investigation (Nagaraja et al., J Clin Invest. 2013; 123:558. doi:10.1172/JCI67887).
More general comments for this study are available on Forbes.com Pharma & Healthcare section.
Source: J Clin Invest, 2013 Jan 25. pii: 63324. doi: 10.1172/JCI63324. [Epub ahead of print]
Updates
A 2018 study by Weikun Qian et al. demonstrated that norepinephrine or noradrenaline (NE) may enhance the malignant biological behaviors of pancreatic ductal adenocarcinoma (PDAC) via activating the Notch‑1 pathway.
Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of cancer, which is associated with a poor prognosis due to complexities in prevention, early diagnosis and effective treatment. The Notch‑1 pathway is widely considered to be a critical tumor‑promoting factor in PDAC.
The Notch-1 pathway is involved in several physical and pathological biological processes, including cancer. Notably, Notch is essential for embryonic development of the pancreas and is involved in the plasticity of adult exocrine cells; in addition, abnormal activation of the Notch-1 pathway is correlated with the initiation and progression of PDAC. Previous studies reported that chronic stress inhibits differentiation, and maintains the stem cell state of hematopoietic stem cells via activating the Notch-1 pathway.
The 2018 study by Weikun Qian et al. indicated that the stress neuromediator NE may activate the Notch-1 pathway in PDAC and promote its malignant biological behaviors; this may be an important factor in its development and be associated with a specific underlying mechanism in the progression of PDAC.
Another 2018 study by Ming-Bing Xiao et al. showed that the β2-adrenergic receptor (β2-AR) regulates the expression of AKR1B1 in human pancreatic cancer cells and promotes their proliferation via the ERK1/2 pathway.
Background: Psychological stress has been recognized as a well-documented risk factor associated with the β2-AR in the development of pancreatic cancer. Aldo–keto reductase 1 member B1 (AKR1B1) is a potential interacting partner of β2-AR, but the effect of their interaction on pancreatic cancer cells is not known at present.
The study by Ming-Bing Xiao et al found that the β2-AR directly interacted with and up-regulated AKR1B1 in pancreatic cancer cells, and promoted their proliferation and inhibited apoptosis via the ERK1/2 pathway. The authors concluded that these results suggest that the β2-AR-AKR1B1 axis as a potential therapeutic target for pancreatic cancer.
A 2021 study by Ping Wang et al. demonstrated that curcumin effectively alleviated the invasion of glioma promoted by adverse psychological stress through inhibiting the MAPK/ERK signaling pathway, which reduced the expression of CD147 and MMP‐2/9. Also, curcumin induced cell cycle changes and increased apoptosis and then inhibited cell proliferation.
Background: Psychological stress promotes the production of catecholamines, such as norepinephrine (NE) and epinephrine (EPI), by activating the sympathetic nervous system (SNS). These stress hormones could promote the growth and invasion of various tumors, including ovarian, pancreatic and breast cancer.
Curcumin is a polyphenolic compound found in the rhizome of turmeric plants, which has various biological effects, including anti‐inflammatory, anti‐oxidation and anti‐infection effects. Curcumin can penetrate the blood‐brain barrier, so it has a good therapeutic effect on primary central nervous system tumours including GBM. Curcumin has been shown to play an anti‐GBM role through regulation of proliferation, apoptosis, metastasis, invasion, autophagy and potential molecular targets, including Wnt/β‐catenin, JAK/STAT3, NF‐κB and MAPK.
Schematic illustration of the underlying mechanism of curcumin inhibited glioma proliferation and invasion with NE stimulation.
The 2021 study by Ping Wang et al. reported that curcumin not only inhibited the growth of xenografts in chronically stressed nude mice, but also decreased the expression of matrix metalloproteinase (MMP)‐2/9 and CD147 in tumor tissues. Exogenous NE was used to stimulate glioma cells to simulate the stress environment in vitro, and it was found that curcumin inhibited the NE‐induced proliferation and invasion of glioma cells in a dose‐dependent manner.
The authors also reported that the effects of NE on glioma cells could lead to the activation of the mitogen‐activated protein kinase (MAPK) signaling pathway through β‐adrenergic receptor, while curcumin suppressed the level of extracellular signal–regulated kinase (ERK)1/2 phosphorylation. The authors concluded that curcumin may be a promising drug for preventing and treating the progression of glioma due to adverse psychological stress.
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