Mechanisms of redox metabolism and cancer cell survival during extracellular matrix detachment

Hawk, Mark A.; Schafer, Zachary T.

doi:10.1074/jbc.tm117.000260

Cited by 70 publications

(44 citation statements)

References 62 publications

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“…Nontransformed cells that become detached from the extracellular matrix (ECM) undergo dysregulation of redox homeostasis and cell death [6] . Cancer cells often acquire the ability to recalibrate the redox balance to survive after ECM detachment, facilitating metastatic dissemination.…”

Section: Discussionmentioning

confidence: 99%

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Nicotinamide nucleotide transhydrogenase-mediated redox homeostasis promotes tumor growth and metastasis in gastric cancer

Zhang

et al. 2018

Redox Biology

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Overcoming oxidative stress is a critical step for tumor growth and metastasis, however the underlying mechanisms in gastric cancer remain unclear. In this study, we found that overexpression of nicotinamide nucleotide transhydrogenase (NNT) was associated with shorter overall and disease free survival in gastric cancer. The NNT is considered a key antioxidative enzyme based on its ability to regenerate NADPH from NADH. Knockdown of NNT caused significantly NADPH reduction, induced high levels of ROS and significant cell apoptosis under oxidative stress conditions such as glucose deprival and anoikis. In vivo experiments showed that NNT promoted tumor growth, lung metastasis and peritoneal dissemination of gastric cancer. Moreover, intratumoral injection of NNT siRNA significantly suppressed gastric tumor growth in patient-derived xenograft (PDX) models. Overall, our study highlights the crucial functional roles of NNT in redox regulation and tumor progression and thus raises an important therapeutic hypothesis in gastric cancer.

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Section: Discussionmentioning

confidence: 99%

“…However, its molecular mechanism has not been clear elucidated. Growing evidence points to the fundamental role of redox homeostasis in tumorigenesis and metastatic progression [5] , [6] , [7] . Yet, the regulation of NADPH metabolism in GC remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Nicotinamide nucleotide transhydrogenase-mediated redox homeostasis promotes tumor growth and metastasis in gastric cancer

Zhang

et al. 2018

Redox Biology

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“…As the first step of metastasis, the detachment of the extracellular matrix (ECM) triggers a series of integrated stress, for instance, a deficiency of glucose uptake, ATP limitation, and oxidative stress (Schafer et al, 2009). Correspondingly, tumor cells utilize several methods to overcome these challenges, including mitigating programmed cell death and recalibrating the redox balance (Hawk and Schafer, 2018).…”

Section: Introductionmentioning

confidence: 99%

Metastatic Melanoma Cells Rely on Sestrin2 to Acquire Anoikis Resistance via Detoxifying Intracellular ROS

Zhu

Guo

et al. 2020

Journal of Investigative Dermatology

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Distant metastases are responsible for the majority of melanoma mortalities. As a critical barrier against metastasis, anoikis is a distinct programmed cell death induced by the integrated stress from extracellular matrix (ECM) detachment. In order to survive, tumor cells employ various strategies for overcoming this barrier. Recently, Sesn2 has been reported to play a protective role against integrated stress. In this study, we found that ECM detachment triggered the upregulation of Sesn2 in metastatic melanoma cells. The knockdown of Sesn2 impaired not only the cell viability but also the tumor sphere formation of melanoma cells in suspension cultures. Moreover, an elevated oxidative stress level was detected in Sesn2-silencing melanoma cells in suspension cultures, accompanied with an increased apoptosis rate. Finally, in vivo studies indicated that the Sesn2-knockdown reduced the formation of distant metastasis remarkably. Taken together, our findings illustrated that the upregulation of Sesn2 in response to suspension stress plays a protective role in melanoma against anoikis by detoxifying oxidative stress.

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“…However, a number of studies have revealed that ECM-detachment can result in cellular changes that compromise cell viability independently of anoikis. These include the activation of novel types of cell death (Overholtzer et al, 2007), enhanced autophagy (Avivar-Valderas et al, 2011;Fung et al, 2008), the induction of mitophagy , and elevated production of reactive oxygen species (ROS) (Davison et al, 2013;Hawk and Schafer, 2018;Jiang et al, 2016). Perhaps most important when considering viability, we have previously demonstrated that ECM-detachment causes fundamental changes in cell metabolism that that can kill cells in the absence of anoikis induction (Schafer et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

SGK1 Signaling Promotes Glucose Metabolism and Survival in Extracellular Matrix Detached Cells

Mason

Cockfield

Pape

et al. 2020

Preprint

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Loss of integrin-mediated attachment to extracellular matrix (ECM) proteins can trigger a variety of cellular changes that impact cell viability. Foremost among these is the activation of anoikis, caspase-mediated cell death induced by ECM-detachment. In addition to anoikis, loss of ECM-attachment causes profound alterations in cellular metabolism that can lead to anoikis-independent cell death. Here, we describe a surprising role for serum and glucocorticoid kinase-1 (SGK1) in the promotion of energy production when cells are detached. Our data demonstrate that SGK1 activation is necessary and sufficient for ATP generation during ECM-detachment and anchorageindependent growth. More specifically, SGK1 promotes a substantial elevation in glucose uptake due to elevated GLUT1 transcription. In addition, carbon flux into the pentose phosphate pathway (PPP) is necessary to accommodate elevated glucose uptake and PPP-mediated glyceraldehyde-3-phosphate (G3P) is necessary for ATP production.Thus, our data unmask SGK1 as master regulator of glucose metabolism and cell survival during ECM-detached conditions.

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Mechanisms of redox metabolism and cancer cell survival during extracellular matrix detachment

Cited by 70 publications

References 62 publications

Nicotinamide nucleotide transhydrogenase-mediated redox homeostasis promotes tumor growth and metastasis in gastric cancer

Nicotinamide nucleotide transhydrogenase-mediated redox homeostasis promotes tumor growth and metastasis in gastric cancer

Metastatic Melanoma Cells Rely on Sestrin2 to Acquire Anoikis Resistance via Detoxifying Intracellular ROS

SGK1 Signaling Promotes Glucose Metabolism and Survival in Extracellular Matrix Detached Cells

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