Search

Abstract: Aim: To explore the cooperation of GLP‐1 receptor and β3‐adrenergic receptor (β3‐AR)‐mediated signalling in the control of fat mass/feeding behaviour by studying the effects of a combined therapy composed of the GLP‐1R agonist liraglutide and the β3‐AR agonist CL316243. Methods: The study included the analysis of key mechanisms regulating lipid/cholesterol metabolism, and thermogenesis in brown (BAT) and epididymal white (eWAT) adipose tissues, abdominal muscle and liver of male rats. Results: CL316243 (1 mg kg−1) and liraglutide (100 μg kg−1) co‐administration over 6 days potentiated an overall negative energy balance (reduction in food intake, body weight gain, fat/non‐fat mass ratio, liver fat content, and circulating levels of non‐essential fatty acids, triglycerides, very low‐density lipoprotein‐cholesterol and leptin). These effects were accompanied by increased plasma levels of insulin and IL6. We also observed increased gene expression of uncoupling proteins regulating thermogenesis in BAT/eWAT (Ucp1) and muscle (Ucp2/3). Expression of transcription factor and enzymes involved either in de novo lipogenesis (Chrebp, Acaca, Fasn, Scd1, Insig1, Srebp1) or in fatty acid β‐oxidation (Cpt1b) was enhanced in eWAT and/or muscle but decreased in BAT. Pparα and Pparγ, essentials in lipid flux/storage, were decreased in BAT/eWAT but increased in the muscle and liver. Cholesterol synthesis regulators (Insig2, Srebp2, Hmgcr) were particularly over‐expressed in muscle. These GLP‐1R/β3‐AR‐induced metabolic effects were associated with the downregulation of cAMP‐dependent signalling pathways (PKA/AKT/AMPK). Conclusion: Combined activation of GLP‐1 and β3‐ARs potentiate changes in peripheral pathways regulating lipid/cholesterol metabolism in a tissue‐specific manner that favours a switch in energy availability/expenditure and may be useful for obesity treatment. [ABSTRACT FROM AUTHOR]

Objectives: To compare mortality rates between GCA patients and the general population in Spain, and to identify associated factors influencing mortality., Methods: ARTESER, a multicenter registry by the Spanish Society of Rheumatology, includes GCA patients from June 2013 to March 2019. Demographic, clinical, imaging, histological and mortality data were collected retrospectively. Only patients with at least one year of follow-up were included for analysis. The mortality rates were expressed as the number of deaths per 1000 person-years, with 95% confidence interval (CI) by sex and age group. Kaplan-Meier method was performed for survival analysis. The factors influencing mortality were analyzed using Cox regression model., Results: A total of 1200 patients with GCA were analyzed, with a mean (SD) follow-up of 2.18 (1.53) years. The overall five-year cumulative mortality rate (95%CI) was 37.86 (31.75-43.96) per 1000 patients/year. The cumulative mortality rate was significantly higher in males than females (59.04vs29.06; p<0.001). The age- and sex-adjusted cumulative mortality rate was similar to the Spanish general population (19.75vs20.72;p=0.559). In the multivariate analysis, older age (HR 1.11, 95%CI 1.073-1.142) and male sex (HR 1.775, 95%CI 1.214-2.594) were associated with increased mortality. Headache (HR 0.55, 95%CI 0.362-0.843) and high hemoglobin levels (HR 0.85, 95%CI 0.744-0.970) were protective factors against death., Conclusions: The overall five-year age- and sex-adjusted cumulative mortality rate in GCA is similar compared to the general population. Older age and male sex appear to be associated with an increased risk of mortality, whereas headache and high hemoglobin levels might serve as protective factors against death., Competing Interests: Declarations. Ethics approval and consent to participate: The study protocol was approved by the Ethics Committee for Research with Medicines of Cantabria, Santander, Spain (No. 05/2019). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. Competing interests: Juan Molina-Collada has received consultancy/speaker’s fees from AbbVie, Lilly, Janssen, Novartis, Pfizer, UCB, MSD, and BMS. None of these fees were related to the present manuscript. Ricardo Blanco received grants/research support from AbbVie, MSD, and Roche, and had consultation fees/participation in a company-sponsored speaker’s bureau from AbbVie, Pfizer, Roche, Lilly, UCB, Bristol-Myers, Janssen, and MSD. Eugenio de Miguel received research funding/consulting and conferences fees from: Abbvie, Novartis, Roche, Pfizer, Janssen, Lilly, MSD, BMS, UC Pharma, Grünenthal and Sanofi. Carlota L Iñiguez received support and speaker's fees from Pfizer, AbbVie, Fresenius - Kiabi, Novartis, GSK, Sanofi y Janssen., (© 2025. The Author(s).)

Over the past decade, new in vitro biological models have emerged which can reproduce certain characteristics of human physiology and pathologies. From organoids to organs-on-chips, these new technologies are currently revolutionizing the entire chain of research and development in pharmacology. All stakeholders are thus involved, from academic laboratories to pharmaceutical companies, start-ups, and assessment agencies. By providing better predictability, these new human biomimetic models also help address societal and ethical challenges regarding the place and use of animals in biomedical research. In this context, participants at the Ateliers de Giens (Giens Workshops) roundtable wished to examine the issues related to these new technologies with their various expertise and, given the stakes involved in the medicine and pharmacology of the future, formulate several recommendations aimed at strengthening the national structuring of the academic and industrial sector, therefore accelerating the development and validation of these new models., Competing Interests: Disclosure of interest The authors declare that they have no competing interest., (Copyright © 2024. Published by Elsevier Masson SAS.)

Competing Interests: Déclaration de liens d’intérêts Les auteurs déclarent ne pas avoir de liens d’intérêts.

The access of non-resident patients to the deceased donor waiting list (DDWL) poses different challenges. The European Committee on Organ Transplantation of the Council of Europe (CD-P-TO) has studied this phenomenon in the European setting. A questionnaire was circulated among the Council of Europe member states to inquire about the criteria applied for non-residents to access their DDWL. Information was compiled from 28 countries. Less than 1% of recipients of deceased donor organs were non-residents. Two countries never allow non-residents to access the DDWL, four allow access without restrictions and 22 only under specific conditions. Of those, most give access to non-resident patients already in their jurisdictions who are in a situation of vulnerability (urgent life-threatening conditions). In addition, patients may be given access: (i) after assessment by a specific committee (four countries); (ii) within the framework of official cooperation agreements (15 countries); and (iii) after patients have officially lived in the country for a minimum length of time (eight countries). The ethical and legal implications of these policies are discussed. Countries should collect accurate information about residency status of waitlisted patients. Transparent criteria for the access of non-residents to DDWL should be clearly defined at national level., (© 2021 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Breast cancer continues to be one of the main causes of morbidity and mortality globally and was the leading cause of cancer death in women in Spain in 2020. Early diagnosis is one of the most effective methods to lower the incidence and mortality rates of breast cancer. The human metalloproteinases (MMP) mainly function as proteolytic enzymes degrading the extracellular matrix and plays important roles in most steps of breast tumorigenesis. This retrospective cohort study shows the immunohistochemical expression levels of MMP-1, MMP-2, MMP-3, and MMP-9 in 154 women with breast cancer and 42 women without tumor disease. The samples of breast tissue are assessed using several tissue matrices (TMA). The percentages of staining (≤50%->50%) and intensity levels of staining (weak, moderate, or intense) are considered. The immunohistochemical expression of the MMP-1-intensity ( p = 0.043) and MMP-3 percentage ( p = 0.018) and intensity, ( p = 0.025) present statistically significant associations with the variable group (control-case); therefore, expression in the tumor tissue samples of these MMPs may be related to the development of breast cancer. The relationships between these MMPs and some clinicopathological factors in breast cancer are also evaluated but no correlation is found. These results suggest the use of MMP-1 and MMP-3 as potential biomarkers of breast cancer diagnosis.

Heme oxygenase-1 (HO-1) is an antioxidant protein implicated in tumor progression, metastasis, and resistance to therapy. Elevated HO-1 expression is associated with stemness in several types of cancer, although this aspect has not yet been studied in colorectal cancer (CRC). Using an in vitro model, we demonstrated that HO-1 overexpression regulates stemness and resistance to 5-FU treatment, regardless of p53. In samples from CRC patients, HO-1 and endothelin converting enzyme-1 (ECE-1) expression correlated significantly, and p53 had no influence on this result. Carbon monoxide (CO) activated the ECE-1/endothelin-1 (ET-1) pathway, which could account for the protumoral effects of HO-1 in p53 wild-type cells, as demonstrated after treatment with bosentan (an antagonist of both ETRA and ETRB endothelin-1 receptors). Surprisingly, in cells with a non-active p53 or a mutated p53 with gain-of-function, ECE-1-produced ET-1 acted as a protective molecule, since treatment with bosentan led to increased efficiency for spheres formation and percentage of cancer stem cells (CSCs) markers. In these cells, HO-1 could activate or inactivate certain unknown routes that could induce these contrary responses after treatment with bosentan in our cell model. However more research is warranted to confirm these results. Patients carrying tumors with a high expression of both HO-1 and ECE-1 and a non-wild-type p53 should be considered for HO-1 based-therapies instead of ET-1 antagonists-based ones.

Pancreatic cancer is one of the most lethal cancers worldwide due to its symptoms, early metastasis, and chemoresistance. Thus, the mechanisms contributing to pancreatic cancer progression require further exploration. Circadian rhythms are the daily oscillations of multiple biological processes regulated by an endogenous clock. Several evidences suggest that the circadian clock may play an important role in the cell cycle, cell proliferation and apoptosis. In addition, timing of chemotherapy or radiation treatment can influence the efficacy and toxicity treatment. Here, we revisit the studies on circadian clock as an emerging target for therapy in pancreatic cancer. We highlight those potential circadian genes regulators that are commonly affected in pancreatic cancer according to most recent reports., (Copyright © 2020 García-Costela, Escudero-Feliú, Puentes-Pardo, San Juán, Morales-Santana, Ríos-Arrabal, Carazo and León.)

Breast cancer (BC) is the most common tumour in women and one of the most important causes of cancer death worldwide. Radiation therapy (RT) is widely used for BC treatment. Some proteins have been identified as prognostic factors for BC (Ki67, p53, E-cadherin, HER2). In the last years, it has been shown that variations in the expression of MMPs and TIMPs may contribute to the development of BC. The aim of this pilot work was to study the effects of RT on different MMPs (-1, -2, -3, -7, -8, -9, -10, -12 and -13) and TIMPs (-1 to -4), as well as their relationship with other variables related to patient characteristics and tumour biology. A group of 20 BC patients treated with RT were recruited. MMP and TIMP serum levels were analysed by immunoassay before, during and after RT. Our pilot study showed a slight increase in the levels of most MMP and TIMP with RT. However, RT produced a significantly decrease in TIMP-1 and TIMP-3 levels. Significant correlations were found between MMP-3 and TIMP-4 levels, and some of the variables studied related to patient characteristics and tumour biology. Moreover, MMP-9 and TIMP-3 levels could be predictive of RT toxicity. For this reason, MMP-3, MMP-9, TIMP-3 and TIMP-4 could be used as potential prognostic and predictive biomarkers for BC patients treated with RT., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Background: Obesity is a low-grade inflammation condition that facilitates the development of numerous comorbidities and the dysregulation of brain homeostasis. Additionally, obesity also causes distinct behavioral alterations both in humans and rodents. Here, we investigated the effect of inducible genetic deletion of the cannabinoid type 1 receptor (CB1) in adipocytes (Ati-CB1-KO mice) on obesity-induced memory deficits, depressive-like behavior, neuroinflammation and adult neurogenesis., Methods: Behavioral, mRNA expression and immunohistochemical studies were performed in Ati-CB1-KO mice and corresponding wild-type controls under standard and high-fat diet., Results: Adipocyte-specific CB1 deletion reversed metabolic disturbances associated with an obese condition confirming previous studies. As compared to obese mice, the metabolic amelioration in Ati-CB1-KO mice was associated with an improvement of mood-related behavior and recognition memory, concomitantly with an increase in cell proliferation in metabolic relevant neurogenic niches in hippocampus and hypothalamus. In mutant mice, these changes were related to an increased neuronal maturation/survival in the hippocampus. Furthermore, CB1 deletion in adipocytes was sufficient to reduce obesity-induced inflammation, gliosis and apoptosis in a brain region-specific manner., Conclusions: Overall our data provide compelling evidence of the physiological relevance of the adipocyte-brain crosstalk where adipocyte-specific CB1 influences obesity-related cognitive deficits and depression-like behavior, concomitantly with brain remodeling, such as adult neurogenesis and neuroinflammation in the hippocampus and hypothalamus., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Breast cancer is the most common cancer in women. Radiotherapy (RT) is one of the mainstay treatments for cancer but in some cases is not effective. Cancer stem cells (CSCs) within the tumor can be responsible for recurrence and metastasis after RT. Matrix metalloproteases (MMPs), regulated mainly by tissue inhibitors of metalloproteinases (TIMPs) and histone deacetylases (HDACs), may also contribute to tumor development by modifying its activity after RT. The aim of this work was to study the effects of RT on the expression of MMPs, TIMPs and HDACs on different cell subpopulations in MCF-7, MDA-MB-231 and SK-BR-3 cell lines. We assessed the in vitro expression of these genes in different 3D culture models and induced tumors in female NSG mice by orthotopic xenotransplants. Our results showed that gene expression is related to the cell subpopulation studied, the culture model used and the single radiation dose administered. Moreover, the crucial role played by the microenvironment in terms of cell interactions and CSC plasticity in tumor growth and RT outcome is also shown, supporting the use of higher doses (6 Gy) to achieve better control of tumor development.

Previous findings demonstrate a homeostatic role for oleoylethanolamide (OEA) signaling in the ethanol-related neuroinflammation and behavior. However, extensive research is still required in order to unveil the effects of OEA on a number of neurobiological functions such as adult neurogenesis, cell survival and resident neuroimmunity that become notably altered by alcohol. Daily consumption of ethanol (10%) for 2 weeks (6.3&#x202F;±&#x202F;1.1&#x202F;g/kg/day during last 5 days) caused hypolocomotor activity in rats. This effect appears to rely on central signaling mechanisms given that alcohol increased the OEA levels, the gene expression of OEA-synthesizing enzyme Nape-pld and the number of PPARα-immunoreactive neurons in the striatum. Ethanol-related neurobiological alterations such as a reduction in the number of microglial cells expressing iNOS (a cytokine-inducible immune defense) and in adult neural stem/progenitor cell (NSPC) proliferation (phospho-H3 and BrdU) and maturation (BrdU/β3-tubulin), as well as an increase in damage cell activity (FosB) and apoptosis (cleaved caspase 3) were also observed in the rat striatum. Pharmacological administration of OEA (10 mg/kg) for 5 days during ethanol exposure exacerbated ethanol-induced hypolocomotion and cell apoptosis in the striatum. Interestingly, OEA abrogated the impaired effects of ethanol on PPARα-positive cell population and NSPC proliferation and maturation. OEA also decreased astrocyte-related vimentin immunoreactivity and increased microglial cell population (Iba-1, iNOS) in the striatum. These results suggest that OEA-PPARα signaling modulates glial activation, cell apoptosis and NSPC proliferation and maturation in response to striatal-specific neurobiological alterations induced by prolonged ethanol intake in rats., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Protective mechanisms against drug-induced liver injury are actively being searched to identify new therapeutic targets. Among them, the anti-inflammatory N -acyl ethanolamide (NAE)-peroxisome proliferators activated receptor alpha (PPARα) system has gained much interest after the identification of its protective role in steatohepatitis and liver fibrosis. An overdose of paracetamol (APAP), a commonly used analgesic/antipyretic drug, causes hepatotoxicity, and it is being used as a liver model. In the present study, we have analyzed the impact of APAP on the liver NAE-PPARα system. A dose-response (0.5-5-10-20 mM) and time-course (2-6-24 h) study in human HepG2 cells showed a biphasic response, with a decreased PPAR α expression after 6-h APAP incubation followed by a generalized increase of NAE-PPARα system-related components ( PPAR α, NAPE-PLD , and FAAH ), including the NAEs oleoyl ethanolamide (OEA) and docosahexaenoyl ethanolamide, after a 24-h exposure to APAP. These results were partially confirmed in a time-course study of mice exposed to an acute dose of APAP (750 mg/kg). The gene expression levels of Ppar α and Faah were decreased after 6 h of treatment and, after 24 h, the gene expression levels of Nape-pld and Faah , as well as the liver levels of OEA and palmitoyl ethanolamide, were increased. Repeated APAP administration (750 mg/kg/day) up to 4 days also decreased the expression levels of PPARα and FAAH, and increased the liver levels of NAEs. A resting period of 15 days completely restored these impairments. Liver immunohistochemistry in a well-characterized human case of APAP hepatotoxicity confirmed PPARα and FAAH decrements. Histopathological and hepatic damage ( Cyp2e1, Caspase3 , α Sma, Tnf α, and Mcp1 )-related alterations observed after repeated APAP administration were aggravated in the liver of Ppar α-deficient mice. Our results demonstrate that the anti-inflammatory NAE-PPARα signaling system is implicated in liver toxicity after exposure to APAP overdose, and may contribute to its recovery through a long-term time-dependent response.

The characterization of colon cancer stem cells (CSCs) may help to develop novel diagnostic and therapeutic procedures. p53 loss increases the pool of CSCs in colorectal cancer (CRC). Recent reports suggest that the oncostatic effects of melatonin could be related to its ability to kill CSCs. Although there are no data linking the loss of p53 function and melatonin synthesis or signaling in cancer, melatonin does activate the p53 tumor-suppressor pathway in this disease. In this work, we analyze whether the expression of melatonin synthesis and signaling genes are related to the expression of CSC markers and the implication of p53 status in samples from patients with CRC. Arylalkylamine N-acetyltransferase (AA-NAT), MT1, and MT2 expression decreased in tumor samples versus normal mucosa samples in mutated p53 (mtp53) tumors versus those with wild-type p53 (wtp53). Further, AA-NAT and MT2 expression were lower in advanced stages of the disease in wtp53 tumors. On the contrary, CD44 and CD66c expression was higher in tumor versus normal mucosa in wtp53 tumors. Additionally, CD44 expression was higher in advanced stages of the disease regardless of the p53 status. Patients with CD44 high CD66c high and wtp53 tumors in advanced stages showed low expression of AA-NAT and MT2 in wtp53 tumors. These results could indicate a possible interaction of these pathways in CRC., Competing Interests: The authors declare no conflict of interest.

To investigate the role of glucagon-like-peptide-1 receptor (GLP-1R) in peripheral lipid metabolism. Both lean and high-fat diet (HFD)-induced obesity (DIO) rats were used to compare the peripheral effects of the subcutaneous and repeated administration of the GLP-1R agonist liraglutide on the expression of key regulators involved in lipid metabolism, β-oxidation and thermogenesis in liver, abdominal muscle, and epididymal white adipose tissue (eWAT). We observed that liraglutide reduced caloric intake, body weight, and plasma levels of triglycerides and VLDL in a diet-independent manner. However, changes in liver fat content and the expression of lipid metabolism regulators were produced in a diet and tissue-dependent manner. In lean rats, liraglutide increased the gene/protein expression of elements involved in lipogenesis (ChREBP, Acaca/ACC, Fasn/FAS, Scd1/SCD1, PPARα/γ), β-oxidation (CPT1b), and thermogenesis (Cox4i1, Ucp1/UCP1) in eWAT and muscle, which suggest an increase in fatty-acid flux and utilization to activate energy expenditure. Regarding DIO rats, the specific reduction of liver lipid content by liraglutide was associated with a decreased expression of main elements involved in lipogenesis (phospho-ACC), peroxisomal β-oxidation (ACOX1), and lipid flux/storage (Pparγ/PPARγ) in liver, which suggest a recovery of lipid homeostasis. Interestingly, the muscle of DIO rats treated with liraglutide showed a decreased expression of PPARγ and the thermogenic factor UCP1. These results help us to better understand the peripheral mechanisms regulating lipid metabolism that underlay the effectiveness of GLP-1 analogues for the treatment of diabetes and obesity. © 2016 BioFactors, 42(6):600-611, 2016., (© 2016 International Union of Biochemistry and Molecular Biology.)

The cannabinoid type 1 (CB 1 ) receptor is widely distributed in the brain and peripheral organs where it regulates cellular functions and metabolism. In the brain, CB 1 is mainly localized on presynaptic axon terminals but is also found on mitochondria (mtCB 1 ), where it regulates cellular respiration and energy production. Likewise, CB 1 is localized on muscle mitochondria, but very little is known about it. The aim of this study was to further investigate in detail the distribution and functional role of mtCB 1 in three different striated muscles. Immunoelectron microscopy for CB 1 was used in skeletal muscles (gastrocnemius and rectus abdominis) and myocardium from wild-type and CB 1 -KO mice. Functional assessments were performed in mitochondria purified from the heart of the mice and the mitochondrial oxygen consumption upon application of different acute delta-9-tetrahydrocannabinol (Δ 9 -THC) concentrations (100 nM or 200 nM) was monitored. About 26% of the mitochondrial profiles in gastrocnemius, 22% in the rectus abdominis and 17% in the myocardium expressed CB 1 . Furthermore, the proportion of mtCB1 versus total CB 1 immunoparticles was about 60% in the gastrocnemius, 55% in the rectus abdominis and 78% in the myocardium. Importantly, the CB 1 immunolabeling pattern disappeared in muscles of CB 1 -KO mice. Functionally, acute 100 nM or 200 nM THC treatment specifically decreased mitochondria coupled respiration between 12 and 15% in wild-type isolated mitochondria of myocardial muscles but no significant difference was noticed between THC treated and vehicle in mitochondria isolated from CB 1 -KO heart. Furthermore, gene expression of key enzymes involved in pyruvate synthesis, tricarboxylic acid (TCA) cycle and mitochondrial respiratory chain was evaluated in the striated muscle of CB 1 -WT and CB 1 -KO. CB 1 -KO showed an increase in the gene expression of Eno3, Pkm2 , and Pdha1 , suggesting an increased production of pyruvate. In contrast, no significant difference was observed in the Sdha and Cox4i1 expression, between CB 1 -WT and CB 1 -KO. In conclusion, CB 1 receptors in skeletal and myocardial muscles are predominantly localized in mitochondria. The activation of mtCB 1 receptors may participate in the mitochondrial regulation of the oxidative activity probably through the relevant enzymes implicated in the pyruvate metabolism, a main substrate for TCA activity.

Interleukin-6 (IL-6) has emerged as an important mediator of fatty acid metabolism with paradoxical effects in the liver. Administration of IL-6 has been reported to confer protection against steatosis, but plasma and tissue IL-6 concentrations are elevated in chronic liver diseases, including fatty liver diseases associated with obesity and alcoholic ingestion. In this study, we further investigated the role of IL-6 on steatosis induced through a high-fat diet (HFD) in wild-type (WT) and IL-6-deficient (IL-6(-/-)) mice. Additionally, HFD-fed IL-6(-/-) mice were also chronically treated with recombinant IL-6 (rIL-6). Obesity in WT mice fed a HFD associated with elevated serum IL-6 levels, fatty liver, upregulation of carnitine palmitoyltransferase 1 (CPT1) and signal transducer and activator of transcription-3 (STAT3), increased AMP kinase phosphorylation (p-AMPK), and downregulation of the hepatic lipogenic enzymes fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1). The HFD-fed IL-6(-/-) mice showed severe steatosis, no changes in CPT1 levels or AMPK activity, no increase in STAT3 amounts, inactivated STAT3, and marked downregulation of the expression of acetyl-CoA carboxylase (ACCα/β), FAS and SCD1. The IL-6 chronic replacement in HFD-fed IL-6 -/-: mice restored hepatic STAT3 and AMPK activation but also increased the expression of the lipogenic enzymes ACCα/β, FAS and SCD1. Furthermore, rIL-6 administration was associated with aggravated steatosis and elevated fat content in the liver. We conclude that, in the context of HFD-induced obesity, the administration of rIL-6 might contribute to the aggravation of fatty liver disease through increasing lipogenesis., (© 2015. Published by The Company of Biologists Ltd.)

Purpose: To evaluate matrix metalloproteinase (MMP) activity and invasion after ionizing radiation (IR) exposure and to determine whether MMP could be epigenetically modulated by histone deacetylase (HDAC) inhibition., Material and Methods: Two human breast cancer cell lines (MDA-MB-231 and MCF-7) were cultured in monolayer (2D) and in laminin-rich extracellular matrix (3D). Invasion capability, collagenolytic and gelatinolytic activity, MMP and TIMP protein and mRNA expression and clonogenic survival were analyzed after IR exposure, with and without a HDAC inhibition treatment [1.5 mM valproic acid (VA) or 1 μM trichostatin-A (TSA)]., Results: IR exposure resulted in cell line-dependent stimulation of invasion capacity. In contrast to MCF-7 cells, irradiated MDA-MB-231 showed significantly enhanced mRNA expression of mmp-1, mmp-3 and mmp-13 and of their regulators timp-1 and timp-2 relative to unirradiated controls. This translated into increased collagenolytic and gelatinolytic activity and could be reduced after valproic acid (VA) treatment. Additionally, VA also mitigated IR-enhanced mmp and timp mRNA expression as well as IR-increased invasion capability. Finally, our data confirm the radiosensitizing effect of VA., Conclusion: These results suggest that IR cell line-dependently induces upregulation of MMP mRNA expression, which appears to be mechanistically linked to a higher invasion capability that is modifiable by HDAC inhibition.