Multifaceted link between cancer and inflammation

2011 ◽  
Vol 32 (1) ◽  
pp. 1-15 ◽  
Author(s):  
Gautam Sethi ◽  
Muthu K. Shanmugam ◽  
Lalitha Ramachandran ◽  
Alan Prem Kumar ◽  
Vinay Tergaonkar
Keyword(s):  
Hypoxia Inducible Factor ◽  
Nuclear Factor Κb ◽  
Activator Protein 1 ◽  
Oxygen Intermediates ◽  
Related Factors ◽  
Preclinical And Clinical Studies ◽  
Tumour Initiation ◽  
Cancer And Inflammation ◽  
Transcription 3

Increasing evidence from epidemiological, preclinical and clinical studies suggests that dysregulated inflammatory response plays a pivotal role in a multitude of chronic ailments including cancer. The molecular mechanism(s) by which chronic inflammation drives cancer initiation and promotion include increased production of pro-inflammatory mediators, such as cytokines, chemokines, reactive oxygen intermediates, increased expression of oncogenes, COX-2 (cyclo-oxygenase-2), 5-LOX (5-lipoxygenase) and MMPs (matrix metalloproteinases), and pro-inflammatory transcription factors such as NF-κB (nuclear factor κB), STAT3 (signal transducer and activator of transcription 3), AP-1 (activator protein 1) and HIF-1α (hypoxia-inducible factor 1α) that mediate tumour cell proliferation, transformation, metastasis, survival, invasion, angiogenesis, chemoresistance and radioresistance. These inflammation-associated molecules are activated by a number of environmental and lifestyle-related factors including infectious agents, tobacco, stress, diet, obesity and alcohol, which together are thought to drive as much as 90% of all cancers. The present review will focus primarily on the role of various inflammatory intermediates responsible for tumour initiation and progression, and discuss in detail the critical link between inflammation and cancer.

scholarly journals Novel insights into the neuroendocrine control of inflammation: the role of GR and PARP1

2014 ◽  
Vol 3 (1) ◽  
pp. R1-R12 ◽  
Author(s):  
Fernando Aprile-Garcia ◽  
María Antunica-Noguerol ◽  
Maia Ludmila Budziñski ◽  
Ana C Liberman ◽  
Eduardo Arzt
Keyword(s):  
Inflammatory Mediators ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Nuclear Factor Κb ◽  
Activator Protein 1 ◽  
Post Translational Modification ◽  
Cytokines And Chemokines ◽  
Inflammatory Processes ◽  
Neuroendocrine Axis

Inflammatory responses are elicited after injury, involving release of inflammatory mediators that ultimately lead, at the molecular level, to the activation of specific transcription factors (TFs; mainly activator protein 1 and nuclear factor-κB). These TFs propagate inflammation by inducing the expression of cytokines and chemokines. The neuroendocrine system has a determinant role in the maintenance of homeostasis, to avoid exacerbated inflammatory responses. Glucocorticoids (GCs) are the key neuroendocrine regulators of the inflammatory response. In this study, we describe the molecular mechanisms involved in the interplay between inflammatory cytokines, the neuroendocrine axis and GCs necessary for the control of inflammation. Targeting and modulation of the glucocorticoid receptor (GR) and its activity is a common therapeutic strategy to reduce pathological signaling. Poly (ADP-ribose) polymerase 1 (PARP1) is an enzyme that catalyzes the addition of PAR on target proteins, a post-translational modification termed PARylation. PARP1 has a central role in transcriptional regulation of inflammatory mediators, both in neuroendocrine tumors and in CNS cells. It is also involved in modulation of several nuclear receptors. Therefore, PARP1 and GR share common inflammatory pathways with antagonic roles in the control of inflammatory processes, which are crucial for the effective maintenance of homeostasis.

scholarly journals Update on the Role of Neuropeptide Y and Other Related Factors in Breast Cancer and Osteoporosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Shu-ting Lin ◽  
Yi-zhong Li ◽  
Xiao-qi Sun ◽  
Qian-qian Chen ◽  
Shun-fa Huang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neuropeptide Y ◽  
Treatment Strategies ◽  
Nuclear Factor Κb ◽  
Breast Cancer Patients ◽  
Related Factors ◽  
Osteogenic Response ◽  
The Relationship

Breast cancer and osteoporosis are common diseases that affect the survival and quality of life in postmenopausal women. Women with breast cancer are more likely to develop osteoporosis than women without breast cancer due to certain factors that can affect both diseases simultaneously. For instance, estrogen and the receptor activator of nuclear factor-κB ligand (RANKL) play important roles in the occurrence and development of these two diseases. Moreover, chemotherapy and hormone therapy administered to breast cancer patients also increase the incidence of osteoporosis, and in recent years, neuropeptide Y (NPY) has also been found to impact breast cancer and osteoporosis.Y1 and Y5 receptors are highly expressed in breast cancer, and Y1 and Y2 receptors affect osteogenic response, thus potentially highlighting a potential new direction for treatment strategies. In this paper, the relationship between breast cancer and osteoporosis, the influence of NPY on both diseases, and the recent progress in the research and treatment of these diseases are reviewed.

scholarly journals NF-κB and AP-1 Connection: Mechanism of NF-κB-Dependent Regulation of AP-1 Activity

2004 ◽  
Vol 24 (17) ◽  
pp. 7806-7819 ◽  
Author(s):  
Shuichi Fujioka ◽  
Jiangong Niu ◽  
Christian Schmidt ◽  
Guido M. Sclabas ◽  
Bailu Peng ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Target Genes ◽  
Nuclear Factor Κb ◽  
Activator Protein 1 ◽  
Murine Embryonic Fibroblast ◽  
Downstream Target ◽  
Iκb Kinase ◽  
Extracellular Signal ◽  
Downstream Target Gene

ABSTRACT Nuclear factor κB (NF-κB) and activator protein 1 (AP-1) transcription factors regulate many important biological and pathological processes. Activation of NF-κB is regulated by the inducible phosphorylation of NF-κB inhibitor IκB by IκB kinase. In contrast, Fos, a key component of AP-1, is primarily transcriptionally regulated by serum responsive factors (SRFs) and ternary complex factors (TCFs). Despite these different regulatory mechanisms, there is an intriguing possibility that NF-κB and AP-1 may modulate each other, thus expanding the scope of these two rapidly inducible transcription factors. To determine whether NF-κB activity is involved in the regulation of fos expression in response to various stimuli, we analyzed activity of AP-1 and expression of fos, fosB, fra-1, fra-2, jun, junB, and junD, as well as AP-1 downstream target gene VEGF, using MDAPanc-28 and MDAPanc-28/IκBαM pancreatic tumor cells and wild-type, IKK1−/−, and IKK2−/− murine embryonic fibroblast cells. Our results show that elk-1, a member of TCFs, is one of the NF-κB downstream target genes. Inhibition of NF-κB activity greatly decreased expression of elk-1. Consequently, the reduced level of activated Elk-1 protein by extracellular signal-regulated kinase impeded constitutive, serum-, and superoxide-inducible c-fos expression. Thus, our study revealed a distinct and essential role of NF-κB in participating in the regulation of elk-1, c-fos, and VEGF expression.

scholarly journals Challenges in Combining Immunotherapy with Radiotherapy in Recurrent/Metastatic Head and Neck Cancer

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3197
Author(s):  
Gaber Plavc ◽  
Tanja Jesenko ◽  
Miha Oražem ◽  
Primož Strojan
Keyword(s):  
Head And Neck ◽  
Checkpoint Inhibitors ◽  
Related Factors ◽  
Cancer Cell Death ◽  
Metastatic Setting ◽  
Active Research ◽  
Preclinical And Clinical Studies ◽  
The Impact ◽  
Selection Of

Immunotherapy with immune checkpoint inhibitors (ICI) has recently become a standard part of the treatment of recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), although the response rates are low. Numerous preclinical and clinical studies have now illuminated several mechanisms by which radiotherapy (RT) enhances the effect of ICI. From RT-induced immunogenic cancer cell death to its effect on the tumor microenvironment and vasculature, the involved mechanisms are diverse and intertwined. Moreover, the research of these interactions is challenging because of the thin line between immunostimulatory and the immunosuppressive effect of RT. In the era of active research of immunoradiotherapy combinations, the significance of treatment and host-related factors that were previously seen as being less important is being revealed. The impact of dose and fractionation of RT is now well established, whereas selection of the number and location of the lesions to be irradiated in a multi-metastatic setting is something that is only now beginning to be understood. In addition to spatial factors, the timing of irradiation is as equally important and is heavily dependent on the type of ICI used. Interestingly, using smaller-than-conventional RT fields or even partial tumor volume RT could be beneficial in this setting. Among host-related factors, the role of the microbiome on immunotherapy efficacy must not be overlooked nor can we neglect the role of gut irradiation in a combined RT and ICI setting. In this review we elaborate on synergistic mechanisms of immunoradiotherapy combinations, in addition to important factors to consider in future immunoradiotherapy trial designs in R/M HNSCC.

scholarly journals Inhibitory Effects of STAT3 Transcription Factor by Synthetic Decoy ODNs on Autophagy in Renal Fibrosis

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 331
Author(s):  
Young-Ah Kim ◽  
Hyun-Ju Kim ◽  
Mi-Gyeong Gwon ◽  
Hyemin Gu ◽  
Hyun-Jin An ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Renal Fibrosis ◽  
Hypoxia Inducible Factor ◽  
Inhibitory Effect ◽  
Immunofluorescent Staining ◽  
Tnf Α ◽  
Factor Α ◽  
Transcription 3 ◽  
Stat3 Decoy

Autophagy in the proximal tubules may promote fibrosis by activating tubular cell death, interstitial inflammation, and the production of pro-fibrotic factors. The signal transducer and activator of transcription 3 (STAT3) is activated as a potential transcription factor, which mediates the stimulation of renal fibrosis. We investigated the role of the STAT3 in autophagy and its effect on the prevention of interstitial renal fibrosis. In this study, we use synthesized STAT3 decoy oligonucleotides (ODN), which were injected into the tail veins of unilateral ureteral obstruction (UUO) mice, to explore the regulation of autophagy in UUO-induced renal fibrosis. The expression of interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and collagen were decreased by STAT3 decoy ODN. The autophagy markers microtubule-associated protein light chain 3 (LC3) and fibronectin, were identified through immunofluorescent staining, indicating that they were reduced in the group injected with ODN. The expressions of LC3, Beclin1, p62, and autophagy-related 5–12 (Atg5–12) and hypoxia inducible factor-1α (HIF-1α) were inhibited in the ODN injection group. We determined the inhibitory effect of autophagy in chronic kidney disease and confirmed that STAT3 decoy ODN effectively inhibited autophagy by inhibiting the expression of STAT3 transcription factors in the UUO group.

scholarly journals Role of β-arrestin1/ERK MAP kinase pathway in regulating adenosine A1 receptor desensitization and recovery

2010 ◽  
Vol 298 (1) ◽  
pp. C56-C65 ◽  
Author(s):  
Sarvesh Jajoo ◽  
Debashree Mukherjea ◽  
Sunny Kumar ◽  
Sandeep Sheth ◽  
Tejbeer Kaur ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
De Novo ◽  
Fold Increase ◽  
Nuclear Factor Κb ◽  
Activator Protein 1 ◽  
De Novo Synthesis ◽  
Ductus Deferens ◽  
A1 Receptor ◽  
Interfering Rna

Exposure of cells to adenosine receptor (AR) agonists leads to receptor uncoupling from G proteins and downregulation of the A1AR. The receptor levels on the cell surface generally recover on withdrawal of the agonist, because of either translocation of the sequestered A1AR back to plasma membrane or de novo synthesis of A1AR. To examine the mechanism(s) underlying A1AR downregulation and recovery, we treated ductus deferens tumor (DDT1 MF-2) cells with the agonist R-phenylisopropyladenosine ( R-PIA) and showed a decrease in membrane A1AR levels by 24 h, which was associated with an unexpected 11-fold increase in A1AR mRNA. Acute exposure of these cells to R-PIA resulted in a rapid translocation of β-arrestin1 to the plasma membrane. Knockdown of β-arrestin1 by short interfering RNA (siRNA) blocked R-PIA-mediated downregulation of the A1AR, suppressed R-PIA-dependent ERK1/2 and activator protein-1 (AP-1) activity, and reduced the induction of A1AR mRNA. Withdrawal of the agonist after a 24-h exposure resulted in rapid recovery of plasma membrane A1AR. This was dependent on the de novo protein synthesis and on the activity of ERK1/2 but independent of β-arrestin1 and nuclear factor-κB. Together, these data suggest that exposure to A1AR agonist stimulates ERK1/2 activity via β-arrestin1, which subserves receptor uncoupling and downregulation, in addition to the induction of A1AR expression. We propose that such a pathway ensures both the termination of the agonist signal and recovery by priming the cell for rapid de novo synthesis of A1AR once the drug is terminated.

scholarly journals Glucocorticoids aggravate hyperoxia-induced lung injury through decreased nuclear factor-κB activity

2003 ◽  
Vol 284 (1) ◽  
pp. L197-L204 ◽  
Author(s):  
Constance Barazzone-Argiroffo ◽  
Alessandra Pagano ◽  
Cristiana Juge ◽  
Isabelle Métrailler ◽  
Anne Rochat ◽  
...  
Keyword(s):  
Lung Injury ◽  
Bronchoalveolar Lavage ◽  
Nuclear Factor Κb ◽  
Lung Damage ◽  
Nuclear Factor ◽  
Activator Protein 1 ◽  
Lung Weight ◽  
Cell Content ◽  
Adrenal Response

We previously reported that exposure of mice to hyperoxia is characterized by extensive lung cell necrosis and apoptosis, mild inflammatory response, and elevated circulating levels of corticosterone. Administration of hydroxycortisone acetate during hyperoxia aggravated lung injury. Using adrenalectomized (ADX) and sham-operated (sham) mice, we studied the role of the glucocorticoids in hyperoxia-induced lung injury. Lung damage was attenuated in ADX mice as measured by lung weight and protein and cell content in bronchoalveolar lavage and as seen by light microscopy. Mortality was delayed by 10 h. Nuclear factor-κB (NF-κB) activity was significantly decreased in lungs of sham mice exposed to hyperoxia but was preserved in ADX mice. There was a correlation between NF-κB activity in ADX mice and decreased levels of IκBα. In contrast, activator protein-1 activity increased similarly in both groups of mice. Levels of interleukin-6 (IL-6), a transcriptional target of NF-κB, were higher in bronchoalveolar lavage and serum of ADX than sham mice. However, the protective effect of ADX was not mediated by IL-6, because administration of recombinant human IL-6 to sham mice did not prevent lung damage. These results demonstrate that the adrenal response aggravates alveolar injury and is likely to be mediated by the decrease of NF-κB function involved in cell survival.

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