International Journal of Molecular Sciences

Research

Jump to: Review

23 pages, 9992 KiB

Open AccessArticle

The Influence of AQP5 on the Response to Hydrogen Peroxide in Breast Cancer Cell Lines

by Ivan Lučić, Monika Mlinarić, Ana Čipak Gašparović and Lidija Milković

Int. J. Mol. Sci. 2025, 26(7), 3243; https://doi.org/10.3390/ijms26073243 - 31 Mar 2025

Viewed by 588

Abstract

Breast cancer is a heterogeneous disease with varying responses to therapies. While targeted treatments have advanced, conventional therapies inducing oxidative stress remain widely used. H₂O₂ has emerged as a therapeutic candidate due to its role in signaling and cell-function regulation. [...] Read more.

Breast cancer is a heterogeneous disease with varying responses to therapies. While targeted treatments have advanced, conventional therapies inducing oxidative stress remain widely used. H₂O₂ has emerged as a therapeutic candidate due to its role in signaling and cell-function regulation. Its transport is tightly regulated through peroxiporins such as AQP5, expression of which is linked to poor prognosis and metastatic spread, and its role in therapy resistance remains underexplored. This study examined AQP5’s role in the acute oxidative stress response. We overexpressed AQP5 in breast cancer cell lines with low basal levels—HR+ (MCF7), HER2+ (SkBr-3), and TNBC (SUM 159)—and exposed them to H₂O₂ for 24 h. We assessed cell viability, intracellular ROS, changes in AQP3 and AQP5, and key antioxidative and cancer-related pathways (NRF2, PI3K/AKT, FOXOs). AQP5 overexpression elicited a cell-type-specific response. H₂O₂ treatment reduced viability in SkBr-3-AQP5 and MCF7-AQP5 cells, increased ROS levels in MCF7-AQP5, and decreased ROS in SUM 159-AQP5. It also increased AQP3 in MCF7-AQP5 and differentially affected NRF2, FOXOs, and PI3K/AKT signaling, notably activating NRF2/AKR1B10 axis in MCF7-AQP5 and decreasing FOXO1 in SUM 159-AQP5. These findings highlight the need for further research into AQP5’s role in the oxidative stress response in breast cancer cells. Full article

(This article belongs to the Special Issue New Players in the Research of Oxidative Stress and Cancer)

► Show Figures

Figure 1

16 pages, 3997 KiB

Open AccessArticle

Triphenylphosphonium-Conjugated Palmitic Acid for Mitochondrial Targeting of Pancreatic Cancer Cells: Proteomic and Molecular Evidence

by Giuliana Siragusa, Jessica Brandi, Tristan Rawling, Michael Murray and Daniela Cecconi

Int. J. Mol. Sci. 2024, 25(12), 6790; https://doi.org/10.3390/ijms25126790 - 20 Jun 2024

Cited by 2 | Viewed by 2079

Abstract

Pancreatic ductal adenocarcinoma (PDAC)’s resistance to therapies is mainly attributed to pancreatic cancer stem cells (PCSCs). Mitochondria-impairing agents can be used to hamper PCSC propagation and reduce PDAC progression. Therefore, to develop an efficient vector for delivering drugs to the mitochondria, we synthesized [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC)’s resistance to therapies is mainly attributed to pancreatic cancer stem cells (PCSCs). Mitochondria-impairing agents can be used to hamper PCSC propagation and reduce PDAC progression. Therefore, to develop an efficient vector for delivering drugs to the mitochondria, we synthesized tris(3,5-dimethylphenyl)phosphonium-conjugated palmitic acid. Triphenylphosphonium (TPP) is a lipophilic cationic moiety that promotes the accumulation of conjugated agents in the mitochondrion. Palmitic acid (PA), the most common saturated fatty acid, has pro-apoptotic activity in different types of cancer cells. TPP-PA was prepared by the reaction of 16-bromopalmitic acid with TPP, and its structure was characterized by ¹H and ¹³C NMR and HRMS. We compared the proteomes of TPP-PA-treated and untreated PDAC cells and PCSCs, identifying dysregulated proteins and pathways. Furthermore, assessments of mitochondrial membrane potential, intracellular ROS, cardiolipin content and lipid peroxidation, ER stress, and autophagy markers provided information on the mechanism of action of TPP-PA. The findings showed that TPP-PA reduces PDAC cell proliferation through mitochondrial disruption that leads to increased ROS, activation of ER stress, and autophagy. Hence, TPP-PA might offer a new approach for eliminating both the primary population of cancer cells and PCSCs, which highlights the promise of TPP-derived compounds as anticancer agents for PDAC. Full article

(This article belongs to the Special Issue New Players in the Research of Oxidative Stress and Cancer)

► Show Figures

Figure 1

24 pages, 10793 KiB

Open AccessArticle

Glutathione Reductase Expression and Its Prognostic Significance in Colon Cancer

by Marlena Brzozowa-Zasada, Adam Piecuch, Karolina Bajdak-Rusinek, Marek Michalski, Olesya Klymenko, Natalia Matysiak, Kamil Janelt and Zenon Czuba

Int. J. Mol. Sci. 2024, 25(2), 1097; https://doi.org/10.3390/ijms25021097 - 16 Jan 2024

Cited by 5 | Viewed by 3017

Abstract

Maintaining a balanced redox state within cells is crucial for the sustenance of life. The process involves continuous cytosolic disulfide reduction reactions to restore oxidized proteins to their reduced thiol forms. There are two main cellular antioxidant pathways—the thioredoxin (Trx) and glutathione (GSH)/glutaredoxin [...] Read more.

Maintaining a balanced redox state within cells is crucial for the sustenance of life. The process involves continuous cytosolic disulfide reduction reactions to restore oxidized proteins to their reduced thiol forms. There are two main cellular antioxidant pathways—the thioredoxin (Trx) and glutathione (GSH)/glutaredoxin (Grx) systems. In the GSH/Grx system, glutathione reductase (GR; GSR) catalyses the reduction of GSH disulfide (GSSG) to its sulfhydryl form (GSH), which can then further reduce oxidized Grxs. GR is an essential enzyme that helps in maintaining the supply of reduced glutathione-GSH, which is a significant reducing thiol found in most cells and known for its antioxidant properties. Therefore, it can have a significant impact on cancer development. To investigate this further, we performed an immunohistochemical analysis of GR protein expression in colon adenocarcinoma samples collected from patients with primary colon adenocarcinoma (stage I and II) and patients with metastasis to regional lymph nodes (stage III). The results of our study revealed a significant relationship between the immunohistochemical expression of GR and tumour histological grade, depth of invasion, regional lymph node involvement, staging, and PCNA immunohistochemical expression. It was found that 95% of patients with stage I had low levels of GR expression, whereas 89% of patients with stage III had high levels of immunohistochemical expression. A high level of expression was also detected in the patients with stage II of the disease, where almost 63% were characterized by a high expression of GR. The Western blot method revealed that the highest level of expression was found in the LS 174T cell line, which corresponds to stage II. The results of our study indicate that the immunohistochemical expression of GR may act as an independent prognostic factor associated with colon adenocarcinoma patients’ prognosis. Full article

(This article belongs to the Special Issue New Players in the Research of Oxidative Stress and Cancer)

► Show Figures

Figure 1

16 pages, 5093 KiB

Open AccessArticle

Glucose Deprivation Induces Cancer Cell Death through Failure of ROS Regulation

by Mingyu Kang, Joon H. Kang, In A. Sim, Do Y. Seong, Suji Han, Hyonchol Jang, Ho Lee, Sang W. Kang and Soo-Youl Kim

Int. J. Mol. Sci. 2023, 24(15), 11969; https://doi.org/10.3390/ijms241511969 - 26 Jul 2023

Cited by 13 | Viewed by 7212

Abstract

In previous work, we showed that cancer cells do not depend on glycolysis for ATP production, but they do on fatty acid oxidation. However, we found some cancer cells induced cell death after glucose deprivation along with a decrease of ATP production. We [...] Read more.

In previous work, we showed that cancer cells do not depend on glycolysis for ATP production, but they do on fatty acid oxidation. However, we found some cancer cells induced cell death after glucose deprivation along with a decrease of ATP production. We investigated the different response of glucose deprivation with two types of cancer cells including glucose insensitive cancer cells (GIC) which do not change ATP levels, and glucose sensitive cancer cells (GSC) which decrease ATP production in 24 h. Glucose deprivation-induced cell death in GSC by more than twofold after 12 h and by up to tenfold after 24 h accompanied by decreased ATP production to compare to the control (cultured in glucose). Glucose deprivation decreased the levels of metabolic intermediates of the pentose phosphate pathway (PPP) and the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) in both GSC and GIC. However, glucose deprivation increased reactive oxygen species (ROS) only in GSC, suggesting that GIC have a higher tolerance for decreased NADPH than GSC. The twofold higher ratio of reduced/oxidized glutathione (GSH/GSSG) in GIS than in GSC correlates closely with the twofold lower ROS levels under glucose starvation conditions. Treatment with N-acetylcysteine (NAC) as a precursor to the biologic antioxidant glutathione restored ATP production by 70% and reversed cell death caused by glucose deprivation in GSC. The present findings suggest that glucose deprivation-induced cancer cell death is not caused by decreased ATP levels, but rather triggered by a failure of ROS regulation by the antioxidant system. Conclusion is clear that glucose deprivation-induced cell death is independent from ATP depletion-induced cell death. Full article

(This article belongs to the Special Issue New Players in the Research of Oxidative Stress and Cancer)

► Show Figures

Figure 1

Review

Jump to: Research

26 pages, 1221 KiB

Open AccessReview

Oxidative Stress and Cancer Therapy: Controlling Cancer Cells Using Reactive Oxygen Species

by Songhyun Ju, Manish Kumar Singh, Sunhee Han, Jyotsna Ranbhise, Joohun Ha, Wonchae Choe, Kyung-Sik Yoon, Seung Geun Yeo, Sung Soo Kim and Insug Kang

Int. J. Mol. Sci. 2024, 25(22), 12387; https://doi.org/10.3390/ijms252212387 - 18 Nov 2024

Cited by 15 | Viewed by 4483

Abstract

Cancer is a multifaceted disease influenced by various mechanisms, including the generation of reactive oxygen species (ROS), which have a paradoxical role in both promoting cancer progression and serving as targets for therapeutic interventions. At low concentrations, ROS serve as signaling agents that [...] Read more.

Cancer is a multifaceted disease influenced by various mechanisms, including the generation of reactive oxygen species (ROS), which have a paradoxical role in both promoting cancer progression and serving as targets for therapeutic interventions. At low concentrations, ROS serve as signaling agents that enhance cancer cell proliferation, migration, and resistance to drugs. However, at elevated levels, ROS induce oxidative stress, causing damage to biomolecules and leading to cell death. Cancer cells have developed mechanisms to manage ROS levels, including activating pathways such as NRF2, NF-κB, and PI3K/Akt. This review explores the relationship between ROS and cancer, focusing on cell death mechanisms like apoptosis, ferroptosis, and autophagy, highlighting the potential therapeutic strategies that exploit ROS to target cancer cells. Full article

(This article belongs to the Special Issue New Players in the Research of Oxidative Stress and Cancer)

► Show Figures

Figure 1

29 pages, 4852 KiB

Open AccessReview

Divergent Processing of Cell Stress Signals as the Basis of Cancer Progression: Licensing NFκB on Chromatin

by Spiros A. Vlahopoulos

Int. J. Mol. Sci. 2024, 25(16), 8621; https://doi.org/10.3390/ijms25168621 - 7 Aug 2024

Cited by 6 | Viewed by 2535

Abstract

Inflammation is activated by diverse triggers that induce the expression of cytokines and adhesion molecules, which permit a succession of molecules and cells to deliver stimuli and functions that help the immune system clear the primary cause of tissue damage, whether this is [...] Read more.

Inflammation is activated by diverse triggers that induce the expression of cytokines and adhesion molecules, which permit a succession of molecules and cells to deliver stimuli and functions that help the immune system clear the primary cause of tissue damage, whether this is an infection, a tumor, or a trauma. During inflammation, short-term changes in the expression and secretion of strong mediators of inflammation occur, while long-term changes occur to specific groups of cells. Long-term changes include cellular transdifferentiation for some types of cells that need to regenerate damaged tissue, as well as death for specific immune cells that can be detrimental to tissue integrity if they remain active beyond the boundaries of essential function. The transcriptional regulator NFκB enables some of the fundamental gene expression changes during inflammation, as well as during tissue development. During recurrence of malignant disease, cell stress-induced alterations enable the growth of cancer cell clones that are substantially resistant to therapeutic intervention and to the immune system. A number of those alterations occur due to significant defects in feedback signal cascades that control the activity of NFκB. Specifically, cell stress contributes to feedback defects as it overrides modules that otherwise control inflammation to protect host tissue. NFκB is involved in both the suppression and promotion of cancer, and the key distinctive feature that determines its net effect remains unclear. This paper aims to provide a clear answer to at least one aspect of this question, namely the mechanism that enables a divergent response of cancer cells to critical inflammatory stimuli and to cell stress in general. Full article

(This article belongs to the Special Issue New Players in the Research of Oxidative Stress and Cancer)

► Show Figures

Figure 1

18 pages, 1910 KiB

Open AccessReview

Lipid Droplet–Mitochondria Contacts in Health and Disease

by Hongjun Fan and Yanjie Tan

Int. J. Mol. Sci. 2024, 25(13), 6878; https://doi.org/10.3390/ijms25136878 - 22 Jun 2024

Cited by 8 | Viewed by 4957

Abstract

The orchestration of cellular metabolism and redox balance is a complex, multifaceted process crucial for maintaining cellular homeostasis. Lipid droplets (LDs), once considered inert storage depots for neutral lipids, are now recognized as dynamic organelles critical in lipid metabolism and energy regulation. Mitochondria, [...] Read more.

The orchestration of cellular metabolism and redox balance is a complex, multifaceted process crucial for maintaining cellular homeostasis. Lipid droplets (LDs), once considered inert storage depots for neutral lipids, are now recognized as dynamic organelles critical in lipid metabolism and energy regulation. Mitochondria, the powerhouses of the cell, play a central role in energy production, metabolic pathways, and redox signaling. The physical and functional contacts between LDs and mitochondria facilitate a direct transfer of lipids, primarily fatty acids, which are crucial for mitochondrial β-oxidation, thus influencing energy homeostasis and cellular health. This review highlights recent advances in understanding the mechanisms governing LD–mitochondria interactions and their regulation, drawing attention to proteins and pathways that mediate these contacts. We discuss the physiological relevance of these interactions, emphasizing their role in maintaining energy and redox balance within cells, and how these processes are critical in response to metabolic demands and stress conditions. Furthermore, we explore the pathological implications of dysregulated LD–mitochondria interactions, particularly in the context of metabolic diseases such as obesity, diabetes, and non-alcoholic fatty liver disease, and their potential links to cardiovascular and neurodegenerative diseases. Conclusively, this review provides a comprehensive overview of the current understanding of LD–mitochondria interactions, underscoring their significance in cellular metabolism and suggesting future research directions that could unveil novel therapeutic targets for metabolic and degenerative diseases. Full article

(This article belongs to the Special Issue New Players in the Research of Oxidative Stress and Cancer)

► Show Figures

Figure 1

17 pages, 1934 KiB

Open AccessReview

Peroxiporins in Triple-Negative Breast Cancer: Biomarker Potential and Therapeutic Perspectives

by Anita Bijelić, Tajana Silovski, Monika Mlinarić and Ana Čipak Gašparović

Int. J. Mol. Sci. 2024, 25(12), 6658; https://doi.org/10.3390/ijms25126658 - 17 Jun 2024

Cited by 3 | Viewed by 1969

Abstract

Triple-negative breast cancer (TNBC) remains one of the most challenging subtypes since it is initially characterized by the absence of specific biomarkers and corresponding targeted therapies. Advances in methodology, translational informatics, genomics, and proteomics have significantly contributed to the identification of therapeutic targets. [...] Read more.

Triple-negative breast cancer (TNBC) remains one of the most challenging subtypes since it is initially characterized by the absence of specific biomarkers and corresponding targeted therapies. Advances in methodology, translational informatics, genomics, and proteomics have significantly contributed to the identification of therapeutic targets. The development of innovative treatments, such as antibody–drug conjugates and immune checkpoint inhibitors, alongside chemotherapy, has now become the standard of care. However, the quest for biomarkers defining therapy outcomes is still ongoing. Peroxiporins, which comprise a subgroup of aquaporins, which are membrane pores facilitating the transport of water, glycerol, and hydrogen peroxide, have emerged as potential biomarkers for therapy response. Research on peroxiporins reveals their involvement beyond traditional channeling activities, which is also reflected in their cellular localization and roles in cellular signaling pathways. This research on peroxiporins provides fresh insights into the mechanisms of therapy resistance in tumors, offering potential avenues for predicting treatment outcomes and tailoring successful TNBC therapies. Full article

(This article belongs to the Special Issue New Players in the Research of Oxidative Stress and Cancer)

► Show Figures

Graphical abstract

Journal Menu

Journal Browser

New Players in the Research of Oxidative Stress and Cancer

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (8 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI