Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells

Kim, Yeon Soo; Vallur, Piyushi Gupta; Jones, Victoria; Worley, Beth L.; Shimko, Sara; Shin, Dong-Woo; Crawford, LaTaijah C.; Chen, Chi‐Wei; Aird, Katherine M.; Abraham, Thomas; Shepherd, Trevor G.; Warrick, Joshua I.; Lee, Nam Y.; Phaëton, Rébécca; Mythreye, Karthikeyan; Hempel, Nadine

doi:10.1038/s41388-019-1097-7

Cited by 36 publications

(23 citation statements)

References 52 publications

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“…As mentioned above, antioxidant enzymes often display dichotomous expression and have context-dependent roles within cancer cells [6,[8][9][10], which are similarly observed for GPx3. Several studies have demonstrated that loss of GPx3 expression within tumor tissues is associated with poor patient prognosis and chemotherapeutic resistance (Table 1) [61][62][63]86,87,[109][110][111][112][113][114][115].…”

Section: Altered Gpx3 Expression and Role In Tumor Tissuesmentioning

confidence: 78%

“…Hence, many antioxidant enzymes were originally classified as tumor suppressors [6]. Conversely, it has been demonstrated that many cancer cells require oxidant scavenging and the upregulation of antioxidant enzyme expression for tumor progression and metastasis [8][9][10][11][12][13][14]. These dichotomous roles of antioxidants at different tumor stages highlight the need for additional studies investigating the role, interplay and regulation of antioxidant enzymes in cancer.…”

Section: Introductionmentioning

confidence: 99%

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Extracellular Glutathione Peroxidase GPx3 and Its Role in Cancer

Chang

Worley

Phaëton

et al. 2020

Cancers

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120

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Mammalian cells possess a multifaceted antioxidant enzyme system, which includes superoxide dismutases, catalase, the peroxiredoxin/thioredoxin and the glutathione peroxidase systems. The dichotomous role of reactive oxygen species and antioxidant enzymes in tumorigenesis and cancer progression complicates the use of small molecule antioxidants, pro-oxidants, and targeting of antioxidant enzymes as therapeutic approaches for cancer treatment. It also highlights the need for additional studies to investigate the role and regulation of these antioxidant enzymes in cancer. The focus of this review is on glutathione peroxidase 3 (GPx3), a selenoprotein, and the only extracellular GPx of a family of oxidoreductases that catalyze the detoxification of hydro- and soluble lipid hydroperoxides by reduced glutathione. In addition to summarizing the biochemical function, regulation, and disease associations of GPx3, we specifically discuss the role and regulation of systemic and tumor cell expressed GPx3 in cancer. From this it is evident that GPx3 has a dichotomous role in different tumor types, acting as both a tumor suppressor and pro-survival protein. Further studies are needed to examine how loss or gain of GPx3 specifically affects oxidant scavenging and redox signaling in the extracellular tumor microenvironment, and how GPx3 might be targeted for therapeutic intervention.

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Section: Altered Gpx3 Expression and Role In Tumor Tissuesmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Extracellular Glutathione Peroxidase GPx3 and Its Role in Cancer

Chang

Worley

Phaëton

et al. 2020

Cancers

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120

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“…MALAT1, which is frequently upregulated in EOC, also partakes in EMT by interacting with EZH2 and by recruiting chromatin modifiers [ 119 – 121 ] and induces formation of a lncRNA-protein complex containing Smads, SETD2 and PPM1A phosphatase leading to dephosphorylation of Smad2/3 and termination of TGFβ/Smad signaling [ 111 ]. Lastly, an under investigated area of regulation of EMT by TGFβ in the cytoplasm is SMAD’s potential role in mitochondrial function [ 122 ] that has emerged as an important player in regulating ovarian cancer metastasis [ 123 ]. Specifically, SMAD2 interacts with mitofusin2 (MFN2) and Rab and Ras Interactor 1 (RIN1) to promote mitochondrial fusion [ 122 ].…”

Section: Tgfβ Family In Ovarian and Related Cancersmentioning

confidence: 99%

TGFβ signaling networks in ovarian cancer progression and plasticity

Asha

Shonibare

Monavarian

et al. 2021

Clin Exp Metastasis

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Epithelial ovarian cancer (EOC) is a leading cause of cancer-related death in women. Late-stage diagnosis with significant tumor burden, accompanied by recurrence and chemotherapy resistance, contributes to this poor prognosis. These morbidities are known to be tied to events associated with epithelial-mesenchymal transition (EMT) in cancer. During EMT, localized tumor cells alter their polarity, cell–cell junctions, cell–matrix interactions, acquire motility and invasiveness and an exaggerated potential for metastatic spread. Key triggers for EMT include the Transforming Growth Factor-β (TGFβ) family of growth factors which are actively produced by a wide array of cell types within a specific tumor and metastatic environment. Although TGFβ can act as either a tumor suppressor or promoter in cancer, TGFβ exhibits its pro-tumorigenic functions at least in part via EMT. TGFβ regulates EMT both at the transcriptional and post-transcriptional levels as outlined here. Despite recent advances in TGFβ based therapeutics, limited progress has been seen for ovarian cancers that are in much need of new therapeutic strategies. Here, we summarize and discuss several recent insights into the underlying signaling mechanisms of the TGFβ isoforms in EMT in the unique metastatic environment of EOCs and the current therapeutic interventions that may be relevant.

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“…Li et al (2019) have also shown that SIRT3 is an independent favorable prognostic factor for OS in serous OC. SIRT3 has also been found to be crucial for anchorage-independent survival and metastasis of OC cells, and both these processes are known to be critical for OC disease progression (Kim et al, 2019). More importantly, the SIRT3/hypoxia-inducible factor (HIF) axis is significantly involved in the Warburg effect observed in OC cells under treatment with ABT737 (Dong et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

SIRT4 and SIRT6 Serve as Novel Prognostic Biomarkers With Competitive Functions in Serous Ovarian Cancer

Wang

Huang

et al. 2021

Front. Genet.

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Sirtuins (SIRTs) are class III histone deacetylases (HDACs) that include seven members and are widely expressed in mammals. Accumulating evidence shows that sirtuins may have contradictory roles in various malignancies. They mainly participate in metabolic homeostasis, DNA damage repair, cell survival, and differentiation, as well as other cancer-related biological processes. To better understand their prognostic role and biological functions, we used comprehensive bioinformatic analyses to demonstrate the expression and mutation of sirtuin family member genes in ovarian cancer (OC), with a detailed focus on prognostic prediction, including the effectiveness of anti-OC drugs. Furthermore, the co-expression genes of SIRT4 and SIRT6 with contradictory survival prediction values in both overall and progression-free survival (PFS) times were further analyzed through Gene Ontology enrichment and Kyoto Encyclopedia annotation. Additionally, we performed and obtained the immunohistochemical staining patterns of these two biomarkers from the serous OC patient database and clinical patient samples to demonstrate their potential applicability in clinical pathology. According to our findings, SIRT4 and SIRT6 are novel prognostic biomarkers that may serve as contradictory competitors for OC cell survival. They are also sensitive biomarkers for the prediction of Avastin’s anticancer effect. While SIRT4 is related to the immune response during oocyte maturation, SIRT6 participates in immune-related disease pathways and mitochondrial metabolism-mediated DNA translation. These findings contribute to the novel hypothesis that SIRT4 and SIRT6 act as contradictory competitors in the regulation of OC behavior. Further studies are required to validate our hypothesis.

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Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells

Cited by 36 publications

References 52 publications

Extracellular Glutathione Peroxidase GPx3 and Its Role in Cancer

Extracellular Glutathione Peroxidase GPx3 and Its Role in Cancer

TGFβ signaling networks in ovarian cancer progression and plasticity

SIRT4 and SIRT6 Serve as Novel Prognostic Biomarkers With Competitive Functions in Serous Ovarian Cancer

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