The complex interplay between redox dysregulation and mTOR signaling pathway in cancer: A rationale for cancer treatment.

The mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that plays a critical role in regulating cellular processes such as growth, proliferation, and metabolism in healthy cells. Dysregulation of mTOR signaling and oxidative stress have been implicated in various diseases including cancer. This review aims to provide an overview of the current understanding of mTOR and its involvement in cell survival and the regulation of cancer cell metabolism as well as its complex interplay with reactive oxygen species (ROS).

Targeting catalase in cancer.

Healthy cells have developed a sophisticated network of antioxidant molecules to prevent the toxic accumulation of reactive oxygen species (ROS) generated by diverse environmental stresses. On the opposite, cancer cells often exhibit high levels of ROS and an altered levels of antioxidant molecules compared to normal cells. Among them, the antioxidant enzyme catalase plays an essential role in cell defense against oxidative stress through the dismutation of hydrogen peroxide into water and molecular oxygen, and its expression is often decreased in cancer cells.

Targeting ROS in cancer: rationale and strategies.

Reactive oxygen species (ROS) in biological systems are transient but essential molecules that are generated and eliminated by a complex set of delicately balanced molecular machineries. Disruption of redox homeostasis has been associated with various human diseases, especially cancer, in which increased ROS levels are thought to have a major role in tumour development and progression. As such, modulation of cellular redox status by targeting ROS and their regulatory machineries is considered a promising therapeutic strategy for cancer treatment.

The Multifaceted Roles of NRF2 in Cancer: Friend or Foe?

Physiological concentrations of reactive oxygen species (ROS) play vital roles in various normal cellular processes, whereas excessive ROS generation is central to disease pathogenesis. The nuclear factor erythroid 2-related factor 2 (NRF2) is a critical transcription factor that regulates the cellular antioxidant systems in response to oxidative stress by governing the expression of genes encoding antioxidant enzymes that shield cells from diverse oxidative alterations. NRF2 and its negative regulator Kelch-like ECH-associated protein 1 (KEAP1) have been the focus of numerous investigations in elucidating whether NRF2 suppresses tumor promotion or conversely exerts pro-oncogenic effects.

PLA2G2A Phospholipase Promotes Fatty Acid Synthesis and Energy Metabolism in Pancreatic Cancer Cells with Mutation.

Oncogenic K-ras is often activated in pancreatic ductal adenocarcinoma (PDAC) due to frequent mutation (>90%), which drives multiple cellular processes, including alterations in lipid metabolism associated with a malignant phenotype. However, the role and mechanism of the altered lipid metabolism in K-ras-driven cancer remains poorly understood. In this study, using human pancreatic epithelial cells harboring inducible K-rasG12D (HPNE/K-rasG12D) and pancreatic cancer cell lines, we found that the expression of phospholipase A2 group IIA (PLA2G2A) was upregulated by oncogenic K-ras.

Reductive TCA cycle catalyzed by wild-type IDH2 promotes acute myeloid leukemia and is a metabolic vulnerability for potential targeted therapy.

Background: Isocitrate dehydrogenase-2 (IDH2) is a mitochondrial enzyme that catalyzes the metabolic conversion between isocitrate and alpha-ketoglutarate (α-KG) in the TCA cycle. IDH2 mutation is an oncogenic event in acute myeloid leukemia (AML) due to the generation of 2-hydroxyglutarate. However, the role of wild-type IDH2 in AML remains unknown, despite patients with it suffer worse clinical outcome than those harboring mutant type.

Treatment and Survival Outcomes Associated With Platinum Plus Low-Dose, Long-term Fluorouracil for Metastatic Nasopharyngeal Carcinoma.

Importance: The treatment of metastatic nasopharyngeal carcinoma (mNPC) is a major challenge because of drug resistance and the toxic effects of chemotherapy.

Objective: To evaluate the survival and toxicity outcomes and safety associated with the use of a modified low-dose fluorouracil protocol compared with standard regimens recommended in current guidelines for treatment of mNPC.

Design, Setting, And Participants: This retrospective cohort study was based on data retrieved from electronic medical records from Sun Yat-sen University Cancer Center in China for 1397 patients with mNPC diagnosed from January 1, 2006, to December 31, 2017.

The Role of Oncogenes and Redox Signaling in the Regulation of PD-L1 in Cancer.

Tumor cells can evade the immune system via multiple mechanisms, including the dysregulation of the immune checkpoint signaling. These signaling molecules are important factors that can either stimulate or inhibit tumor immune response. Under normal physiological conditions, the interaction between programmed cell death ligand 1 (PD-L1) and its receptor, programmed cell death 1 (PD-1), negatively regulates T cell function.

Wild-type IDH2 protects nuclear DNA from oxidative damage and is a potential therapeutic target in colorectal cancer.

Although the role of isocitrate dehydrogenase (IDH) mutation in promoting cancer development has been well-characterized, the impact of wild-type IDH on cancer cells remains unclear. Here we show that the wild-type isocitrate dehydrogenase 2 (IDH2) is highly expressed in colorectal cancer (CRC) cells, and plays an unexpected role in protecting the cancer cells from oxidative damage. Genetic abrogation of IDH2 in CRC cells leads to reactive oxygen species (ROS)-mediated DNA damage and an accumulation of 8-oxoguanine with DNA strand breaks, which activates DNA damage response (DDR) with elevated γH2AX and phosphorylation of ataxia telangiectasia-mutated (ATM) protein, leading to a partial cell cycle arrest and eventually cell senescence.

Vitamin C (Ascorbate) and Redox Topics in Cancer.

Vitamin C (ascorbate), in regard to its effectiveness against malignancies, has had a controversial history in cancer treatment. It has been shown that and anticancer efficacy of ascorbate relies on its pro-oxidant effect mainly from an increased generation of reactive oxygen species (ROS). A growing understanding of its anticancer activities and pharmacokinetic properties has prompted scientists to re-evaluate the significance of ascorbate in cancer treatment.

Loss of mitochondrial aconitase promotes colorectal cancer progression via SCD1-mediated lipid remodeling.

Objective: Mitochondrial aconitase (ACO2) is an essential enzyme that bridges the TCA cycle and lipid metabolism. However, its role in cancer development remains to be elucidated. The metabolic subtype of colorectal cancer (CRC) was recently established.

Regulation of PD-L1 expression in K-ras-driven cancers through ROS-mediated FGFR1 signaling.

K-ras mutations are major genetic events that drive cancer development associated with aggressive malignant phenotypes, while expression of the immune checkpoint molecule PD-L1 plays a key role in cancer evasion of the immune surveillance that also profoundly affects the patient outcome. However, the relationship between K-ras oncogenic signal and PD-L1 expressions as an important area that requires further investigation. Using both in vitro and in vivo experimental models of K-ras-driven cancer, we found that oncogenic K-ras significantly enhanced PD-L1 expression through a redox-mediated mechanism.

Oncogenic K-ras Induces Mitochondrial OPA3 Expression to Promote Energy Metabolism in Pancreatic Cancer Cells.

K-ras (Kirsten ras GTPase) mutations are oncogenic events frequently observed in many cancer types especially in pancreatic cancer. Although mitochondrial dysfunction has been associated with K-ras mutation, the molecular mechanisms by which K-ras impacts mitochondria and maintains metabolic homeostasis are not fully understood. In this study, we used two K-ras inducible cell systems, human pancreatic epithelial/ K-ras (HPNE/K-ras) and human embryonic kidney cells with tetracycline repressorT-Rex/K-ras, to evaluate the role of oncogenic K-ras in regulating mitochondrial function.

Cancer Cell Sensitivity to Redox-Cycling Quinones is Influenced by NAD(P)H: Quinone Oxidoreductase 1 Polymorphism.

Background: Cancer cell sensitivity to drugs may be associated with disturbed antioxidant enzymes expression. We investigated mechanisms of resistance by using oxidative stress-resistant MCF-7 breast cancer cells (Resox cells). Since nicotinamide adenine dinucleotide phosphate (NAD(P)H): quinone oxidoreductase-1 (NQO1) is modified in tumors and oxidative stress-resistant cells, we studied its role in cells exposed to β-lapachone, menadione, and doxorubicin.

Regulation of CD137 expression through K-Ras signaling in pancreatic cancer cells.

Background: The interaction between CD137 and its ligand (CD137L) plays a major role in the regulation of immune functions and affects cancer immunotherapy. CD137 is a cell surface protein mainly located on activated T cells, and its regulation and functions in immune cells are well established. However, the expression of CD137 and its regulation in cancer cells remain poorly understood.

Targeting hsp90 family members: A strategy to improve cancer cell death.

A crucial process in biology is the conversion of the genetic information into functional proteins that carry out the genetic program. However, a supplementary step is required to obtain functional proteins: the folding of the newly translated polypeptides into well-defined, three-dimensional conformations. Proteins chaperones are crucial for this final step in the readout of genetic information, which results in the formation of functional proteins.

Glucose-regulated protein of 94 kDa contributes to the development of an aggressive phenotype in breast cancer cells.

Grp94 plays an essential role in protein assembly. We previously suggested that Grp94 overexpression is involved in tumor aggressiveness. However, the underlying mechanisms remain unknown.

Impact of Nrf2 on tumour growth and drug sensitivity in oncogenic K-ras-transformed cells in vitro and in vivo.

K-ras is one of the most common oncogenes in human cancers, and its aberrant activation may lead to malignant transformation associated with oxidative stress and activation of the transcription factor Nrf2 that regulates multiple detoxification enzymes. The purpose of this research was to use gene editing technology to evaluate the role of Nrf2 in affecting tumour growth and drug sensitivity of K-ras-transformed cells. We showed that induction of K-ras caused a significant activation of Nrf2 associated with increased expression of its target genes NAD(P)H:quinone oxidoreductase 1 (NQO1) and haem oxygenase-1 (HO-1).

Evaluation of Potential Mechanisms Controlling the Catalase Expression in Breast Cancer Cells.

Development of cancer cell resistance against prooxidant drugs limits its potential clinical use. MCF-7 breast cancer cells chronically exposed to ascorbate/menadione became resistant (Resox cells) by increasing mainly catalase activity. Since catalase appears as an anticancer target, the elucidation of mechanisms regulating its expression is an important issue.

Catalase down-regulation in cancer cells exposed to arsenic trioxide is involved in their increased sensitivity to a pro-oxidant treatment.

Background: Pro-oxidant drugs have been proposed for treating certain cancers but the resistance developed by cancer cells to oxidative stress limits its potential use in clinics. To understand the mechanisms underlying resistance to oxidative stress, we found that the chronic exposure to an HO-generating system (ascorbate/menadione, Asc/Men) or catalase overexpression (CAT3 cells) increased the resistance of cancer cells to oxidative stress, likely by increasing the antioxidant status of cancer cells.

Methods: Modulation of catalase expression was performed by either protein overexpression or protein down-regulation using siRNA against catalase and aminotriazole as pharmacological inhibitor.

Catalase, a remarkable enzyme: targeting the oldest antioxidant enzyme to find a new cancer treatment approach.

This review is centered on the antioxidant enzyme catalase and will present different aspects of this particular protein. Among them: historical discovery, biological functions, types of catalases and recent data with regard to molecular mechanisms regulating its expression. The main goal is to understand the biological consequences of chronic exposure of cells to hydrogen peroxide leading to cellular adaptation.

Chemotherapy induces tumor immune evasion by upregulation of programmed cell death ligand 1 expression in bone marrow stromal cells.

Programmed cell death ligand 1 (PD-L1) is a negative regulator of the immune response that enables tumor cells to escape T-cell immunity. Although PD-L1 expression in cancer cells has been extensively studied, the expression of PD-L1 in stromal cells and its clinical significance remain largely unknown. Here, we show that bone marrow stromal cells express a low level of PD-L1 and that this molecule is significantly upregulated by key drugs used in the treatment of lymphoma at clinically relevant concentrations.