scholarly journals MYCN mediates cysteine addiction and sensitizes to ferroptosis

2021 ◽  
Author(s):  
Hamed Alborzinia ◽  
Andres F. Florez ◽  
Sina Gogolin ◽  
Lena M Brueckner ◽  
Chunxuan Shao ◽  
...  
Keyword(s):  
Tumor Regression ◽  
Redox Balance ◽  
Antioxidant Response ◽  
Poor Clinical Outcome ◽  
Aberrant Expression ◽  
Glutathione Biosynthesis ◽  
Cystathionine Beta Synthase ◽  
Spontaneous Tumor Regression ◽  
Limiting Amino Acid ◽  
Rate Limiting

Aberrant expression of MYC family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYC induces massive lipid peroxidation upon depletion of cysteine, the rate-limiting amino acid for glutathione biosynthesis and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death. In MYCN-amplified childhood neuroblastoma, MYCN mediates resistance to ferroptosis by activating transsulfuration of methionine to cysteine. MYCN may contribute to spontaneous tumor regression in low-risk neuroblastomas by promoting ferroptosis in cells with epigenetically silenced cystathionine-beta-synthase, the rate-limiting enzyme for transsulfuration. We identified enzymes and antiporter proteins crucial to ferroptotic escape, providing multiple previously unknown sites that may be acted on therapeutically.

Spontaneous tumor regression Experimental aspects

Urology ◽  
1974 ◽  
Vol 3 (5) ◽  
pp. 544-551 ◽  
Author(s):  
A.P. McLaughlin ◽  
Ruben F. Gittes
Keyword(s):  
Tumor Regression ◽  
Spontaneous Tumor ◽  
Spontaneous Tumor Regression

scholarly journals Stress Responses in Down Syndrome Neurodegeneration: State of the Art and Therapeutic Molecules

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 266
Author(s):  
Chiara Lanzillotta ◽  
Fabio Di Domenico
Keyword(s):  
Down Syndrome ◽  
Stress Response ◽  
Stress Responses ◽  
Redox Balance ◽  
Antioxidant Response ◽  
Chromosome 21 ◽  
Therapeutic Approaches ◽  
Genomic Disorder ◽  
Therapeutic Molecules ◽  
Early Alzheimer’S Disease

Down syndrome (DS) is the most common genomic disorder characterized by the increased incidence of developing early Alzheimer’s disease (AD). In DS, the triplication of genes on chromosome 21 is intimately associated with the increase of AD pathological hallmarks and with the development of brain redox imbalance and aberrant proteostasis. Increasing evidence has recently shown that oxidative stress (OS), associated with mitochondrial dysfunction and with the failure of antioxidant responses (e.g., SOD1 and Nrf2), is an early signature of DS, promoting protein oxidation and the formation of toxic protein aggregates. In turn, systems involved in the surveillance of protein synthesis/folding/degradation mechanisms, such as the integrated stress response (ISR), the unfolded stress response (UPR), and autophagy, are impaired in DS, thus exacerbating brain damage. A number of pre-clinical and clinical studies have been applied to the context of DS with the aim of rescuing redox balance and proteostasis by boosting the antioxidant response and/or inducing the mechanisms of protein re-folding and clearance, and at final of reducing cognitive decline. So far, such therapeutic approaches demonstrated their efficacy in reverting several aspects of DS phenotype in murine models, however, additional studies aimed to translate these approaches in clinical practice are still needed.

Cancer immunoediting and “spontaneous” tumor regression

2010 ◽  
Vol 206 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Neel Sengupta ◽  
Tammie S. MacFie ◽  
Thomas T. MacDonald ◽  
Daniel Pennington ◽  
Andrew R. Silver
Keyword(s):  
Tumor Regression ◽  
Cancer Immunoediting ◽  
Spontaneous Tumor ◽  
Spontaneous Tumor Regression

scholarly journals Assessing the Role of Potential Biomarkers in Antimony Susceptible and Resistant Clinical Isolates of L. donovani from India

2016 ◽  
Vol 4 (1) ◽  
pp. 1-13
Author(s):  
Mahendra Maharjan ◽  
Swati Mandal ◽  
Rentala Madhubala
Keyword(s):  
Protein A ◽  
Building Blocks ◽  
Underlying Mechanism ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Polyamine Biosynthesis ◽  
Glutathione Biosynthesis ◽  
Antimony Resistance ◽  
Rate Limiting

Failure of antimonial drugs, the mainstay therapy for leishmaniasis has become an escalating problem in the treatment of Indian leishmaniasis. Using 14 clinical isolates from both visceral (VL) and post-kala-azar dermal leismaniasis (PKDL) patients, we have examined the role of ATP-binding cassette transporter (ABC transporter) gene, multidrug resistant protein A (MRPA) and two building blocks of the major thiol, trypanothione namely, ornithine decarboxylase gene (ODC) (a rate limiting enzyme in the polyamine biosynthesis) and γ-glutamylcysteine synthetase (γ-GCS) (a rate limiting enzyme in glutathione biosynthesis) in antimony resistance. Amplification of these three genes was observed in some but not all clinical isolates. Increased expression of the three RNAs as determined by real-time PCR was observed in all SAG-R clinical isolates. Significant increase in cysteine and glutathione levels was observed in the resistant isolates. Our studies report the underlying mechanism of antimony resistance in the clinical isolates.

scholarly journals Mitochondrial Functions, Energy Metabolism and Protein Glycosylation are Interconnected Processes Mediating Resistance to Bortezomib in Multiple Myeloma Cells

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 696 ◽  
Author(s):  
Daniele Tibullo ◽  
Cesarina Giallongo ◽  
Alessandra Romano ◽  
Nunzio Vicario ◽  
Alessandro Barbato ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Mitochondrial Dynamics ◽  
Redox Balance ◽  
Antioxidant Response ◽  
Myeloma Cell ◽  
Protein Glycosylation ◽  
Antioxidant Defenses ◽  
Hexosamine Biosynthetic Pathway ◽  
Multiple Myeloma Cell ◽  
Mitochondrial Functions

The proteasome inhibitor bortezomib (BTZ) has emerged as an effective drug for the treatment of multiple myeloma even though many patients relapse from BTZ therapy. The present study investigated the metabolic pathways underlying the acquisition of bortezomib resistance in multiple myeloma. We used two different clones of multiple myeloma cell lines exhibiting different sensitivities to BTZ (U266 and U266-R) and compared them in terms of metabolic profile, mitochondrial fitness and redox balance homeostasis capacity. Our results showed that the BTZ-resistant clone (U266-R) presented increased glycosylated UDP-derivatives when compared to BTZ-sensitive cells (U266), thus also suggesting higher activities of the hexosamine biosynthetic pathway (HBP), regulating not only protein O- and N-glycosylation but also mitochondrial functions. Notably, U266-R displayed increased mitochondrial biogenesis and mitochondrial dynamics associated with stronger antioxidant defenses. Furthermore, U266-R maintained a significantly higher concentration of substrates for protein glycosylation when compared to U266, particularly for UDP-GlcNac, thus further suggesting the importance of glycosylation in the BTZ pharmacological response. Moreover, BTZ-treated U266-R showed significantly higher ATP/ADP ratios and levels of ECP and also exhibited increased mitochondrial fitness and antioxidant response. In conclusions, our findings suggest that the HBP may play a major role in mitochondrial fitness, driving BTZ resistance in multiple myeloma and thus representing a possible target for new drug development for BTZ-resistant patients.

scholarly journals Cases of Spontaneous Tumor Regression in Hepatobiliary Cancers: Implications for Immunotherapy?

2015 ◽  
Vol 46 (2) ◽  
pp. 161-165 ◽  
Author(s):  
Anna L. Parks ◽  
Ryan M. McWhirter ◽  
Kimberley Evason ◽  
Robin K. Kelley
Keyword(s):  
Tumor Regression ◽  
Spontaneous Tumor ◽  
Spontaneous Tumor Regression

scholarly journals Spontaneous Regression of Advanced Hepatocellular Carcinoma

2020 ◽  
Vol 14 (3) ◽  
pp. 491-496
Author(s):  
Dhiraj J. Sonbare ◽  
Rupal Bandi ◽  
Vivek Sharma ◽  
Thomas Cacciarelli ◽  
Obaid S. Shaikh
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Invasion ◽  
Spontaneous Regression ◽  
Tumor Regression ◽  
Complete Regression ◽  
Advanced Hepatocellular Carcinoma ◽  
Specific Therapy ◽  
Therapeutic Implications ◽  
Spontaneous Tumor Regression ◽  
Related Mortality

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. The tumor carries poor prognosis with curative therapeutic options limited to surgical resection, tumor ablation, and liver transplantation. Rarely, there is spontaneous regression of the tumor. We describe the case of a 74-year-old male with cirrhosis from non-alcoholic steatohepatitis who developed advanced HCC that was associated with tumor invasion of the portal vein and marked elevation of serum alfa-fetoprotein level. The patient received no cancer-specific therapy. However, 1 year after the initial diagnosis, he was noted to have complete regression of the tumor. In this report, we discuss possible mechanisms of spontaneous tumor regression and its therapeutic implications.

Context-Dependent Regulation of Nrf2/ARE Axis on Vascular Cell Function during Hyperglycemic Condition

2020 ◽  
Vol 16 (8) ◽  
pp. 797-806 ◽  
Author(s):  
Tharmarajan Ramprasath ◽  
Allen John Freddy ◽  
Ganesan Velmurugan ◽  
Dhanendra Tomar ◽  
Balakrishnan Rekha ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
High Glucose ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Vascular Dysfunction ◽  
Redox Balance ◽  
Antioxidant Response ◽  
Antioxidant Genes ◽  
Increased Risk ◽  
Context Dependent

: Diabetes mellitus is associated with an increased risk of micro and macrovascular complications. During hyperglycemic conditions, endothelial cells and vascular smooth muscle cells are exquisitely sensitive to high glucose. This high glucose-induced sustained reactive oxygen species production leads to redox imbalance, which is associated with endothelial dysfunction and vascular wall remodeling. Nrf2, a redox-regulated transcription factor plays a key role in the antioxidant response element (ARE)-mediated expression of antioxidant genes. Although accumulating data indicate the molecular mechanisms underpinning the Nrf2 regulated redox balance, understanding the influence of the Nrf2/ARE axis during hyperglycemic condition on vascular cells is paramount. This review focuses on the context-dependent role of Nrf2/ARE signaling on vascular endothelial and smooth muscle cell function during hyperglycemic conditions. This review also highlights improving the Nrf2 system in vascular tissues, which could be a potential therapeutic strategy for vascular dysfunction.

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