Sulfiredoxin inhibitor induces preferential death of cancer cells through reactive oxygen species-mediated mitochondrial damage

Kim, Hojin; Lee, Gong Rak; Kim, Jiwon; Baek, Jin Young; Jo, You Jin; Hong, Seong Ahn; Kim, Sung Hoon; Lee, Jiae; Lee, Hyein; Park, Song Kyu; Kim, Hwan Mook; Lee, Hwa Jeong; Chang, Tong Shin; Rhee, Sue Goo; Lee, Ju Seog; Jeong, Woojin

doi:10.1016/j.freeradbiomed.2015.12.023

Cited by 44 publications

(33 citation statements)

References 51 publications

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“…In malignant human skin tumors, Wei et al showed that SRXN1 inhibition (by the AP-1 pathway) may be a novel strategy for skin cancer prevention and treatment [77]. Kim et al and Kim et al demonstrated that SRXN1 inhibition by synthetic inhibitors (J14 and K27) selectively promotes the death of A549 pulmonary tumor cells [84,85]. All these studies suggest that when SRXN1 activity is inhibited, the high ROS levels exceed cell antioxidant capacity, resulting in accumulated damage that selectively leads to tumor cell death.…”

Section: Discussionmentioning

confidence: 99%

Sulfiredoxin as a Potential Therapeutic Target for Advanced and Metastatic Prostate Cancer

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et al. 2020

Oxidative Medicine and Cellular Longevity

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The incidence of prostate cancer (PCa) is increasing, and it is currently the second most frequent cause of death by cancer in men. Despite advancements in cancer therapies, new therapeutic approaches are still needed for treatment-refractory advanced metastatic PCa. Cross-species analysis presents a robust strategy for the discovery of new potential therapeutic targets. This strategy involves the integration of genomic data from genetically engineered mouse models (GEMMs) and human PCa datasets. Considering the role of antioxidant pathways in tumor initiation and progression, we searched oxidative stress-related genes for a potential therapeutic target for PCa. First, we analyzed RNA-sequencing data from Pb-Cre4; Ptenf/f mice and discovered an increase in sulfiredoxin (Srxn1) mRNA expression in high-grade prostatic intraepithelial neoplasia (PIN), well-differentiated adenocarcinoma (medium-stage tumors), and poor-differentiated adenocarcinoma (advanced-stage prostate tumors). The increase of SRXN1 protein expression was confirmed by immunohistochemistry in mouse prostate tumor paraffin samples. Analyses of human databases and prostate tissue microarrays demonstrated that SRXN1 is overexpressed in a subset of high-grade prostate tumors and correlates with aggressive PCa with worse prognosis and decreased survival. Analyses in vitro showed that SRXN1 expression is also higher in most PCa cell lines compared to normal cell lines. Furthermore, siRNA-mediated downregulation of SRXN1 led to decreased viability of PCa cells LNCaP. In conclusion, we identified the antioxidant enzyme SRXN1 as a potential therapeutic target for PCa. Our results suggest that the use of specific SRXN1 inhibitors may be an effective strategy for the adjuvant treatment of castration-resistant PCa with SRXN1 overexpression.

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Section: Discussionmentioning

confidence: 99%

Sulfiredoxin as a Potential Therapeutic Target for Advanced and Metastatic Prostate Cancer

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et al. 2020

Oxidative Medicine and Cellular Longevity

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“…In general, NRF2 can control multiple metabolic routes by two different mechanisms, similarly to other oncogenes (e.g., MYC or KRAS): the first involves direct transactivation of key metabolic enzymes [222], while the second relies on the modulation of proteins controlling other signaling pathways such as PPARγ [223], Notch [215,224], AHR [225,226] and PI3K/AKT [53]. It is known that alterations of tumor metabolism are often paralleled by an increased antioxidant capacity, which is also part of the adaptive response mounted by cancer cells to face adverse conditions, including OS [173,[227][228][229][230]. With this respect, certain metabolic reactions can play a dual role, providing intermediates for biosynthetic processes or essential cofactors used to modulate the intracellular redox balance [231][232][233][234][235].…”

Section: Metabolic Reprogramming By Nrf2: Nadph Links Tumor Growth Anmentioning

confidence: 99%

Potential Applications of NRF2 Modulators in Cancer Therapy

et al. 2020

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The nuclear factor erythroid 2-related factor 2 (NRF2)–Kelch-like ECH-associated protein 1 (KEAP1) regulatory pathway plays an essential role in protecting cells and tissues from oxidative, electrophilic, and xenobiotic stress. By controlling the transactivation of over 500 cytoprotective genes, the NRF2 transcription factor has been implicated in the physiopathology of several human diseases, including cancer. In this respect, accumulating evidence indicates that NRF2 can act as a double-edged sword, being able to mediate tumor suppressive or pro-oncogenic functions, depending on the specific biological context of its activation. Thus, a better understanding of the mechanisms that control NRF2 functions and the most appropriate context of its activation is a prerequisite for the development of effective therapeutic strategies based on NRF2 modulation. In line of principle, the controlled activation of NRF2 might reduce the risk of cancer initiation and development in normal cells by scavenging reactive-oxygen species (ROS) and by preventing genomic instability through decreased DNA damage. In contrast however, already transformed cells with constitutive or prolonged activation of NRF2 signaling might represent a major clinical hurdle and exhibit an aggressive phenotype characterized by therapy resistance and unfavorable prognosis, requiring the use of NRF2 inhibitors. In this review, we will focus on the dual roles of the NRF2-KEAP1 pathway in cancer promotion and inhibition, describing the mechanisms of its activation and potential therapeutic strategies based on the use of context-specific modulation of NRF2.

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“…Similarly, Srx is highly expressed in poorly differentiated, aggressive HCT116 human colorectal cancer cells, while in normal colon epithelium (NCM460) or cells derived from well-differentiated colorectal carcinomas (SW640 and HT29) this protein was not detected [32]. It has been also observed that inhibition of Srx resulted in selective death of cancer cells by disturbance in redox homeostasis [33]. Taken together, we assume that inhibition of Srx could be considered as a novel approach and target for anticancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Synergisms, Discrepancies and Interactions between Hydrogen Sulfide and Carbon Monoxide in the Gastrointestinal and Digestive System Physiology, Pathophysiology and Pharmacology

2020

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Endogenous gas transmitters, hydrogen sulfide (H2S), carbon monoxide (CO) and nitric oxide (NO) are important signaling molecules known to exert multiple biological functions. In recent years, the role of H2S, CO and NO in regulation of cardiovascular, neuronal and digestive systems physiology and pathophysiology has been emphasized. Possible link between these gaseous mediators and multiple diseases as well as potential therapeutic applications has attracted great attention from biomedical scientists working in many fields of biomedicine. Thus, various pharmacological tools with ability to release CO or H2S were developed and implemented in experimental animal in vivo and in vitro models of many disorders and preliminary human studies. This review was designed to review signaling functions, similarities, dissimilarities and a possible cross-talk between H2S and CO produced endogenously or released from chemical donors, with special emphasis on gastrointestinal digestive system pathologies prevention and treatment.

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Sulfiredoxin inhibitor induces preferential death of cancer cells through reactive oxygen species-mediated mitochondrial damage

Cited by 44 publications

References 51 publications

Sulfiredoxin as a Potential Therapeutic Target for Advanced and Metastatic Prostate Cancer

Sulfiredoxin as a Potential Therapeutic Target for Advanced and Metastatic Prostate Cancer

Potential Applications of NRF2 Modulators in Cancer Therapy

Synergisms, Discrepancies and Interactions between Hydrogen Sulfide and Carbon Monoxide in the Gastrointestinal and Digestive System Physiology, Pathophysiology and Pharmacology

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