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

Kim, Yeon Soo; Gupta-Vallur, Piyushi; Jones, Victoria; Worley, Beth L.; Shimko, Sara; Shin, Dong‐Hui; 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:10.1101/670778

Cited by 7 publications

(18 citation statements)

References 50 publications

(69 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, SIRT3 can increase SOD2 activity to properly regulate ROS production to prevent apoptosis 110 . In ovarian cancer cells, SIRT3 fine-tunes SOD2 activity to adapt to cellular stress and anoikis resistance in order to ensure cell survival 111 . Interestingly, the activation of SOD2 mediated by SIRT3 can promote epithelial-mesenchymal transition (EMT) in triple negative breast cancer (TNBC) cells 25 .…”

Section: Sirt3 and Human Diseasementioning

confidence: 99%

Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target

Zhang¹,

Xiang²,

Liu³

et al. 2020

Theranostics

240

202

View full text Add to dashboard Cite

Sirtuin 3 (SIRT3) is one of the most prominent deacetylases that can regulate acetylation levels in mitochondria, which are essential for eukaryotic life and inextricably linked to the metabolism of multiple organs. Hitherto, SIRT3 has been substantiated to be involved in almost all aspects of mitochondrial metabolism and homeostasis, protecting mitochondria from a variety of damage. Accumulating evidence has recently documented that SIRT3 is associated with many types of human diseases, including age-related diseases, cancer, heart disease and metabolic diseases, indicating that SIRT3 can be a potential therapeutic target. Here we focus on summarizing the intricate mechanisms of SIRT3 in human diseases, and recent notable advances in the field of small-molecule activators or inhibitors targeting SIRT3 as well as their potential therapeutic applications for future drug discovery.

show abstract

Section: Sirt3 and Human Diseasementioning

confidence: 99%

Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target

Zhang¹,

Xiang²,

Liu³

et al. 2020

Theranostics

240

202

View full text Add to dashboard Cite

show abstract

“…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: Alterations In Gpx3 Expression and Activity In Cancermentioning

confidence: 99%

“…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%

Extracellular Glutathione Peroxidase GPx3 and Its Role in Cancer

Chang

Worley

Phaëton

et al. 2020

Cancers

Self Cite

120

View full text Add to dashboard Cite

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.

show abstract

“…In vivo studies have demonstrated that increased antioxidant enzyme expression and small molecule antioxidant treatment promotes the metastatic spread of melanoma and breast cancer cells (Davison et al, 2013;Piskounova et al, 2015), suggesting that the maintenance of redox homeostasis is a key adaptation during metastasis. Similarly, we have shown that ovarian cancer cells increase their mitochondrial antioxidant capacity after matrix detachment, by upregulating the expression and activity of the deacetylase sirtuin 3 (SIRT3), and its target protein the mitochondrial superoxide dismutase SOD2 (Kim et al, 2020). Our previous work demonstrated that SIRT3-dependent SOD2 deacetylation is necessary for SOD2 activity and that upregulation of both SIRT3 and SOD2 are necessary for anoikis resistance and in vivo transcoelomic spread of ovarian cancer cells (Kim et al, 2020).…”

Section: Introductionmentioning

confidence: 96%

“…Similarly, we have shown that ovarian cancer cells increase their mitochondrial antioxidant capacity after matrix detachment, by upregulating the expression and activity of the deacetylase sirtuin 3 (SIRT3), and its target protein the mitochondrial superoxide dismutase SOD2 (Kim et al, 2020). Our previous work demonstrated that SIRT3-dependent SOD2 deacetylation is necessary for SOD2 activity and that upregulation of both SIRT3 and SOD2 are necessary for anoikis resistance and in vivo transcoelomic spread of ovarian cancer cells (Kim et al, 2020).…”

Section: Introductionmentioning

confidence: 96%

HuR-dependent SOD2 protein synthesis is an early adaptation to anchorage independence

Kim

Welles

Tang

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

The presence of malignant ascites is a common feature of advanced stage ovarian cancer. During metastasis, as cells detach from the tumor and extravasate into the peritoneal fluid, ovarian cancer cells must adapt to survive the loss of anchorage support and evade anoikis. An important pro-survival adaptation in this context is the ability of tumor cells to increase their antioxidant capacity and restore cellular redox balance. We previously showed that the mitochondrial superoxide dismutase SOD2 is necessary for ovarian cancer cell anoikis resistance, anchorage-independent survival and spheroid formation, and intraperitoneal spread in vivo. We now demonstrate that the upregulation of SOD2 protein expression is an early event initiated in response to anchorage independence and occurs at the post-transcriptional level. SOD2 protein synthesis is rapidly induced in the cytosol within 2 hours of matrix detachment. Polyribosome profiling demonstrates an increase in the number of ribosomes bound to SOD2 mRNA, indicating an increase in SOD2 translation in response to anchorage-independence. Mechanistically, we find that anchorage-independence induces cytosolic accumulation of the RNA binding protein HuR/ELAVL1, leads to HuR binding to SOD2 mRNA, and that the presence of HuR is necessary for the increase in SOD2 mRNA association with the heavy polyribosome fraction and SOD2 protein synthesis. Cellular detachment activates the stress-response protein kinase p38 MAPK, which is necessary for HuR-SOD2 mRNA binding and the rapid increase in SOD2 protein expression. Moreover, HuR is necessary for optimal cell survival during early stages of anchorage independence. These findings uncover a novel post-transcriptional stress response mechanism by which tumor cells are able to rapidly increase their mitochondrial antioxidant capacity to adapt to stress associated with anchorage-independence.

show abstract

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

Cited by 7 publications

References 50 publications

Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target

Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target

Extracellular Glutathione Peroxidase GPx3 and Its Role in Cancer

HuR-dependent SOD2 protein synthesis is an early adaptation to anchorage independence

Contact Info

Product

Resources

About