The Two Faces of Reactive Oxygen Species in Cancer

“O2− is released into the mitochondrial matrix by complexes I, II, and III, where SOD2 rapidly converts it to H2O2 (Murphy 2009).”

“Although primarily localized to the plasma membrane, NOXs can be found on other membranes, including those of the nucleus, mitochondria, and endoplasmic reticulum (Bedard & Krause 2007).”

“Although oncogene activation, enhanced metabolism, and hypoxia can increase ROS production, tumor suppressor loss can diminish ROS elimination (Schieber & Chandel 2014).”

“However, during hypoxia, the HIF-α protein is allowed to dimerize with the HIF-β subunit and translocate to the nucleus to induce expression of proangiogenic genes, such as vascular endothelial growth factor and genes involved in cell survival, glycolysis, and metastasis (Semenza 2003, 2012).”

“Because high levels of ROS can cause damage to lipids, proteins, and DNA, it was thought that ROS were oncogenic, promoting genomic instability and tumorigenesis (Ames et al. 1993).”

“Thus, the ROS-induced PI3K/Akt survival pathway has been shown to be activated in a majority of cancers (Cantley 2002).”

“ROS accumulation can occur because ROS production is increased or ROS elimination is decreased (Trachootham et al. 2009).”

“This results in an increase in NADPH generation and maintenance of the cellular antioxidant capacity to counterbalance the hypoxia-induced increase in mitochondrial ROS (mROS) (Kim et al. 2006, Ye et al. 2014).”

“However, during hypoxia, the HIF-α protein is allowed to dimerize with the HIF-β subunit and translocate to the nucleus to induce expression of proangiogenic genes, such as vascular endothelial growth factor and genes involved in cell survival, glycolysis, and metastasis (Semenza 2003, 2012).”

“Although these results are promising, several large-scale, prospective clinical studies have shown that dietary antioxidant supplementation with β-carotene, vitamin A, or vitamin E increased the incidence of cancer (Klein et al. 2011, Omenn et al. 1996).”

“Normally, NRF2 is targeted for proteasomal degradation through its interaction with the cytoplasmic protein Kelchlike ECH-associated protein 1 (KEAP1) and the Cul3-based E3 ubiquitin ligase (Ishii et al. 2000, Itoh et al. 1999, Kobayashi et al. 2004).”

“Enhanced ROS scavenging due to NRF2-mediated gene expression in cancer cells likely maintains ROS homeostasis by preventing ROS-mediated activation of the death-inducing JNK/p38 pathways and irreversible oxidative damage.”

“ROS also promote tumor cell survival through the activation of NF-κB and NRF2, transcription factors that upregulate the expression of antioxidants to evade ROS-mediated cancer cell death (Kobayashi & Yamamoto 2006, Morgan & Liu 2011).”

“Thus, it is not surprising that several human cancers, including breast and liver cancers, overexpress SLC7A11 to maintain their antioxidant capacity and evade ferroptosis ( Jiang et al. 2015).”

“Under normoxic conditions (ample oxygen), HIF-α is degraded following PHD2-mediated hydroxylation and subsequent recognition by the E3 ubiquitin ligase von Hippel–Lindau protein (Kaelin & Ratcliffe 2008).”

“Low levels of ROS can activate signaling pathways to regulate metabolic adaptation, differentiation, and cellular proliferation in a controlled manner (Sena & Chandel 2012).”

“Additionally, it is conceivable that the thiol-containing compounds GSH or reduced TRX recycle the oxidized scavenger back to its reduced state and transmit the signal to the target protein (Shao et al. 2014).”

“This therapeutic approach may be particularly beneficial for targeting cancer stem cells (CSCs), a highly tumorigenic subpopulation of cancer cells often resistant to chemotherapy and ionizing radiation (Meacham & Morrison 2013, Yang et al. 2016).”

“…mid-1990s demonstrated that ROS promote tumorigenesis (Safford et al. 1994, St. Clair et al. 1992), and oncogenic Ras and growth factor signaling can induce H2O2 activation of the PI3K/Akt/mTOR and MAPK/ERK signaling cascades (Figure 3) (Bae et al. 1997, Irani et al. 1997, Sundaresan et al. 1995).”

“…oxidation of TRX causes ASK1 dissociation and activation, thereby triggering the suppression of anti-apoptotic factors through the sustained activation of the downstream MAP kinase kinase (MKK)4/MKK7/JNK and MKK3/MKK6/p38 pathways (Ichijo et al. 1997, Saitoh et al. 1998, Tobiume et al. 2001).”

“H2O2 is the best described signaling molecule (Finkel 2011, Reczek & Chandel 2015).”

“When ROS levels are too high, cell cycle arrest, senescence, and cancer cell death can occur (Ichijo et al. 1997, Moon et al. 2010).”

“NOX-derived ROS promote the formation of invadopodia, plasma membrane protrusions that tumor cells use to invade (Diaz et al. 2009).”

“Normally, NRF2 is targeted for proteasomal degradation through its interaction with the cytoplasmic protein Kelchlike ECH-associated protein 1 (KEAP1) and the Cul3-based E3 ubiquitin ligase (Ishii et al. 2000, Itoh et al. 1999, Kobayashi et al. 2004).”

“However, it is now appreciated that ROS can also serve as signaling molecules to regulate numerous physiological and biological responses, including growth factor signaling, proliferation, and adaptation to hypoxia (Holmstrom & Finkel 2014, Schieber & Chandel 2014).”

“Moreover, through the induction of the metabolic gene TIGAR, p53 can control antioxidant function (Bensaad et al. 2006; Cheung et al. 2012, 2013).”

“However, when p53 is lost or mutated, as observed in more than 50% of human cancers, ROS accumulation can occur, allowing for protumorigenic signaling and cellular transformation (Levine & Oren 2009).”

“These species have long been viewed as exclusively toxic molecules, inducing pathologies such as cancer (Cross et al. 1987).”

“F or p er so na l u se o nl y. regulate Kras-induced anchorage-independent growth of lung cancer cells through the MAPK/ERK pathway (Weinberg et al. 2010).”

“In addition, one-carbon metabolism is required for nucleotide synthesis (Locasale 2013).”

“Additionally, buthionine sulfoximine (BSO), an inhibitor of glutamate cysteine ligase (GCL), the enzyme required for GSH synthesis, depletes GSH and exhibits anticancer activity (Andringa et al. 2006, Bailey et al. 1997, Griffith & Meister 1979).”

“Compared with normal cells, cancer cells have an increased production of spatially localized ROS that hyperactivates the cell signaling pathways necessary for cellular transformation and tumorigenesis (Figure 2) (Sabharwal & Schumacker 2014).”

“…mid-1990s demonstrated that ROS promote tumorigenesis (Safford et al. 1994, St. Clair et al. 1992), and oncogenic Ras and growth factor signaling can induce H2O2 activation of the PI3K/Akt/mTOR and MAPK/ERK signaling cascades (Figure 3) (Bae et al. 1997, Irani et al. 1997, Sundaresan et al. 1995).”

“Normally, NRF2 is targeted for proteasomal degradation through its interaction with the cytoplasmic protein Kelchlike ECH-associated protein 1 (KEAP1) and the Cul3-based E3 ubiquitin ligase (Ishii et al. 2000, Itoh et al. 1999, Kobayashi et al. 2004).”

“Elevated ROS levels resulting from mutations in mitochondrial DNA that impair complex I activity have also been shown to promote the metastasis of mouse and human tumor cell lines (Ishikawa et al. 2008).”

“F or p er so na l u se o nl y. and inactivate proteins containing iron–sulfur clusters (Fridovich 1997), SODs are located in various cellular compartments to rapidly convert O2− to H2O2.”

“Furthermore, human melanoma cells require the NADPH-generating enzymes of the folate-mediated one-carbon metabolism pathway to promote distant metastasis (Piskounova et al. 2015).”

“ROS also oxidize and inactivate MAPK phosphatases, inducing growth factor receptor activation and MAPK/ERK pro-proliferative signaling (Seth & Rudolph 2006, Son et al. 2011).”

“…oxidation of TRX causes ASK1 dissociation and activation, thereby triggering the suppression of anti-apoptotic factors through the sustained activation of the downstream MAP kinase kinase (MKK)4/MKK7/JNK and MKK3/MKK6/p38 pathways (Ichijo et al. 1997, Saitoh et al. 1998, Tobiume et al. 2001).”

“For example, CD44v-expressing human gastrointestinal CSCs have been shown to stabilize the cysteine-glutamate exchange transporter and increase the synthesis of GSH (Ishimoto et al. 2011).”

“Dietary supplementation of the antioxidant NAC reduced tumor growth in a p53-deficient mouse model (Sablina et al. 2005).”

“To raise the antioxidant capacity and prevent ROS-mediated tumor cell death, AMPK is activated to promote NADPH production and prevent anabolic processes that require NADPH consumption ( Jeon et al. 2012).”

“Therefore, targeting specific, NRF2-regulated, NADPH-producing metabolic pathways may be a more effective approach to anticancer therapeutics (DeNicola et al. 2015, Fan et al. 2014, Labuschagne et al. 2014, Lewis et al. 2014).”

“CAT can very efficiently convert H2O2 to H2O and O2 in the absence of any cofactors in the peroxisomes of most cells.”

“Excessive levels of ROS can increase oxidative stress and induce cancer cell death (Nogueira et al. 2008, Trachootham et al. 2006).”

“PTEN and PTP1B, negative regulators of PI3K/Akt signaling (Lee et al. 2002, Salmeen et al. 2003).”

“Additionally, complex III can release O2− into the intermembrane space, allowing O2− to traverse through voltage-dependent anion channels into the cytosol and be converted into H2O2 by SOD1 (Han et al. 2003, Muller et al. 2004).”

“As tumor cells detach from the extracellular matrix and invade the basement membrane, ROS levels increase and the reduced pool of GSH decreases (Schafer et al. 2009).”

“Because cancer cells rapidly consume serine to promote proliferation, manipulating nutrient availability may be a promising therapeutic strategy (Maddocks et al. 2013).”

“Genetic loss of the modifier subunit of GCL (known as GCLM) or BSO administration prior to tumor onset has been shown to impair mammary tumor initiation and progression in vivo (Harris et al. 2015).”

“Importantly, eukaryotic PRXs can be transiently inactivated when a second H2O2 molecule reversibly hyperoxidizes it to sulfinic acid (SO2−) and can be reactivated by the enzymatic activity of sulfiredoxin (Biteau et al. 2003, Woo et al. 2003).”

“PTEN and PTP1B, negative regulators of PI3K/Akt signaling (Lee et al. 2002, Salmeen et al. 2003).”

“Recently, a high dose of the antioxidant vitamin C has been shown to function as a pro-oxidant (ROS generator), genotype-selective anticancer agent, inducing the cell death of Kras- and Braf-mutant colon cancer cells (Yun et al. 2015).”

“In the absence of SIRT3, SOD2 activity is decreased, resulting in ROS accumulation, HIF-1α protein stabilization, and tumorigenesis (Bell et al. 2011, Finley et al. 2011, Kim et al. 2010, Tao et al. 2010).”

“H2O2 is the best described signaling molecule (Finkel 2011, Reczek & Chandel 2015).”

“Consistent with these findings, NAC and vitamin E supplementation markedly accelerated tumor development and mortality in mouse models of Kras- and Braf-induced lung cancer (Sayin et al. 2014).”

“ROS also promote tumor cell survival through the activation of NF-κB and NRF2, transcription factors that upregulate the expression of antioxidants to evade ROS-mediated cancer cell death (Kobayashi & Yamamoto 2006, Morgan & Liu 2011).”

“O2− has also been shown to function in redox signaling and the initiation of cell death (Buetler et al. 2004, Chen et al. 2009).”

“In the absence of SIRT3, SOD2 activity is decreased, resulting in ROS accumulation, HIF-1α protein stabilization, and tumorigenesis (Bell et al. 2011, Finley et al. 2011, Kim et al. 2010, Tao et al. 2010).”

“In the absence of SIRT3, SOD2 activity is decreased, resulting in ROS accumulation, HIF-1α protein stabilization, and tumorigenesis (Bell et al. 2011, Finley et al. 2011, Kim et al. 2010, Tao et al. 2010).”

“Excessive levels of ROS can increase oxidative stress and induce cancer cell death (Nogueira et al. 2008, Trachootham et al. 2006).”

“Therefore, targeting specific, NRF2-regulated, NADPH-producing metabolic pathways may be a more effective approach to anticancer therapeutics (DeNicola et al. 2015, Fan et al. 2014, Labuschagne et al. 2014, Lewis et al. 2014).”

“For example, the SOD1 inhibitor ATN-224 has been shown to induce cell death in various 90 Reczek · Chandel A nn u.”

“Moreover, CSCs maintain survival and their stem-like properties by upregulating numerous ROS-dependent signaling pathways, such as the PI3K/Akt/mTOR and Notch pathways (McAuliffe et al. 2012, Zhou et al. 2007).”

“F or p er so na l u se o nl y. (Bigarella et al. 2014); therefore, it will be important to identify and target the specific antioxidant pathways selectively used by cancer cells to maintain redox balance.”

“Growth factor receptor stimulation increases NOX-derived H2O2 production and Src kinase activation, resulting in phosphorylation and inactivation of PRX1 (Woo et al. 2010).”

“Redox relay has been well characterized in yeast (the Orp1–Yap1 redox relay) (D’Autreaux & Toledano 2007) and, more recently, in mammalian cells (the PRX2–STAT3 redox relay) (Sobotta et al. 2015).”

“NRF2 constitutive upregulation has been observed in many cancer types, including skin, breast, prostate, and lung (No et al. 2014).”

“To detoxify H2O2, PRXs serve as oxidant acceptors; their active site cysteine residues can undergo H2O2-mediated oxidation (Rhee et al. 2012).”

“To support anchorage-independent growth and avoid cell death during metastasis, cancer cells undergo metabolic changes to increase their antioxidant capacity ( Jiang et al. 2016, Piskounova et al. 2015).”

“Therefore, targeting specific, NRF2-regulated, NADPH-producing metabolic pathways may be a more effective approach to anticancer therapeutics (DeNicola et al. 2015, Fan et al. 2014, Labuschagne et al. 2014, Lewis et al. 2014).”

“F or p er so na l u se o nl y. murine models (Porporato et al. 2014).”

“Hypoxia-induced mROS stabilizes the oxygen-sensitive HIF-α subunit by inhibiting PHD2 activity (Bell et al. 2007).”

“In a recent study, oncogenic Kras-derived mROS activated NF-κB through PKD1 to upregulate pro-proliferative EGFR signaling, leading to the formation of pancreatic precancerous lesions (Liou et al. 2016).”

“Importantly, eukaryotic PRXs can be transiently inactivated when a second H2O2 molecule reversibly hyperoxidizes it to sulfinic acid (SO2−) and can be reactivated by the enzymatic activity of sulfiredoxin (Biteau et al. 2003, Woo et al. 2003).”

“Furthermore, the oncogenic activation of Akt can increase ROS production to further promote cancer cell survival and proliferation (Behrend et al. 2003, Los et al. 2009).”

“HIF-α stabilization through a ROS-dependent mechanism has been shown to promote the tumorigenesis of certain cancer cells (Gao et al. 2007, Horak et al. 2010, Ma et al. 2009).”

“One mechanism for promoting target protein oxidation by H2O2 may rely on the ability of ROS scavenging enzymes to sense and transduce the H2O2 signal (Winterbourn 2013).”

“PTEN is frequently inactivated in numerous human cancers, including glioblastomas, melanoma, prostate, breast, and endometrial cancers (Wu et al. 2003).”

“F or p er so na l u se o nl y. cells (Giannoni et al. 2005).”

“ROS-mediated activation of the JNK and p38 signaling pathways can also induce cell cycle arrest, preventing cancer cell growth and division (Ambrosino & Nebreda 2001, Thornton & Rincon 2009, Wagner & Nebreda 2009).”

“To survive and proliferate in this harsh tumor microenvironment, cancer cells undergo metabolic changes that include HIF stabilization and the activation of the AMPK and one-carbon metabolism pathways to enhance NADPH production and maintain redox balance ( Jeon et al. 2012, Ye et al. 2014).”

“Indeed, the loss of AMPK has been shown to prevent oncogenic transformation (Bardeesy et al. 2002, Laderoute et al. 2006).”

“In the absence of SIRT3, SOD2 activity is decreased, resulting in ROS accumulation, HIF-1α protein stabilization, and tumorigenesis (Bell et al. 2011, Finley et al. 2011, Kim et al. 2010, Tao et al. 2010).”

“Although primarily localized to the plasma membrane, NOXs can be found on other membranes, including those of the nucleus, mitochondria, and endoplasmic reticulum (Bedard & Krause 2007).”

“Moreover, p38 MAPK has been characterized as a tumor suppressor, inhibiting oncogenic Hras malignant transformation (Dolado et al. 2007).”

“F or p er so na l u se o nl y. cysteine residues in KEAP1 can undergo H2O2 oxidation, preventing NRF2 association and subsequent degradation (Fourquet et al. 2010).”

“Thus, not surprisingly, one-carbon metabolism is upregulated and required for cancer cell proliferation (Kim et al. 2015, Labuschagne et al. 2014, Nilsson et al. 2014, Ye et al. 2014).”

“Moreover, NRF2 activation can promote NADPH production by regulating enzymes in the PPP and serine biosynthesis pathways (DeNicola et al. 2015, Wu et al. 2011).”

“Signaling-associated ROS are produced from two main sources, the mitochondria and membranebound NADPH oxidases (NOXs) (Figure 1) (Brewer et al. 2015, Goncalves et al. 2015).”

“Oncogenic mutations in Ras can lead to increased ROS production from NOX4 to enhance proliferation (Ogrunc et al. 2014).”

“Additionally, in a recent study, BSO delivered in combination with the glucose analog 2-deoxy-D-glucose (2DG) selectively induced the cell death of metabolically reprogrammed mutant Kras copy gain–specific lung cancer cells in vitro and in vivo (Kerr et al. 2016).”

“NADPH abundance has also been found to negatively correlate with sensitivity to ferroptosis-inducing compounds (Shimada et al. 2016).”

“Enhanced ROS scavenging due to NRF2-mediated gene expression in cancer cells likely maintains ROS homeostasis by preventing ROS-mediated activation of the death-inducing JNK/p38 pathways and irreversible oxidative damage.”

“…mid-1990s demonstrated that ROS promote tumorigenesis (Safford et al. 1994, St. Clair et al. 1992), and oncogenic Ras and growth factor signaling can induce H2O2 activation of the PI3K/Akt/mTOR and MAPK/ERK signaling cascades (Figure 3) (Bae et al. 1997, Irani et al. 1997, Sundaresan et al. 1995).”

“Inactivating mutations in p38 and JNK pathway components have been observed in numerous human tumors, suggesting that these signaling pathways promote cancer cell death (Han & Sun 2007, Kennedy & Davis 2003).”

“In a recent study, oncogenic Kras-derived mROS activated NF-κB through PKD1 to upregulate pro-proliferative EGFR signaling, leading to the formation of pancreatic precancerous lesions (Liou et al. 2016).”

“SOD1 and SOD3 rapidly convert NOX-derived O2− into H2O2, which can readily diffuse across membranes to impinge on cellular signaling (Fisher 2009).”

“Moreover, through the induction of the metabolic gene TIGAR, p53 can control antioxidant function (Bensaad et al. 2006; Cheung et al. 2012, 2013).”

“Indeed, NRF2 has been shown to be essential for cancer cell proliferation and tumorigenesis (DeNicola et al. 2011, Jaramillo & Zhang 2013, Satoh et al. 2013).”

“Additionally, it is conceivable that the thiol-containing compounds GSH or reduced TRX recycle the oxidized scavenger back to its reduced state and transmit the signal to the target protein (Shao et al. 2014).”

“The heightened antioxidant capacity of CSCs not only allows for CSC self-renewal and differentiation, but also allows CSCs to evade ROS-mediated oxidative damage and cell death induced by radiation and conventional chemotherapy (Diehn et al. 2009).”

“A proton relay recently been described to increase the sensitivity of GAPDH to H2O2 (Peralta et al. 2015).”

“Furthermore, a synthetic lethal screen with small molecules identified the compound lanperisone, a selective killer of Kras-mutant cancer cells that increased the steady-state levels of ROS (Shaw et al. 2011).”

“F or p er so na l u se o nl y. non-small-cell lung cancer cells, including those with an oncogenic Kras mutation, through the ROS-dependent activation of the p38/MAPK signaling pathway and the subsequent downregulation of the anti-apoptotic factor myeloid cell leukemia 1 (Glasauer et al. 2014).”

“It is possible that dietary antioxidants do not efficiently scavenge the pool of protumorigenic signaling ROS and instead promote tumor progression by decreasing the toxicity of ROS distant from their site of production (Figure 4) (Chandel & Tuveson 2014).”

“…a recent high-throughput screen of 635,000 small molecules against mitochondrial H2O2 production revealed three compounds that specifically suppress complex III O2− production and prevent HIF-1α protein stabilization without impairing the bioenergetic function of the mitochondria (Orr et al. 2015).”

“HIF-α stabilization through a ROS-dependent mechanism has been shown to promote the tumorigenesis of certain cancer cells (Gao et al. 2007, Horak et al. 2010, Ma et al. 2009).”

“Moreover, targeting the antioxidant CAT in combination with ROS-generating CDK4 and CDK6 inhibitors has been shown to elevate ROS levels above the threshold and reduce pancreatic ductal adenocarcinoma cell growth (Franco et al. 2016).”

“Moreover, through the induction of the metabolic gene TIGAR, p53 can control antioxidant function (Bensaad et al. 2006; Cheung et al. 2012, 2013).”

“For example, mitochondrial PRX3 has been shown to be reversibly hyperoxidized and inactivated by cytochrome P450–derived H2O2 during corticosterone synthesis in mice (Kil et al. 2012).”

“, HIF and Snail) to enhance cancer cell migration and invasion (Tochhawng et al. 2013).”

“H2O2 has been shown to reversibly oxidize critical cysteine thiol groups of phosphatases, including PTEN, PTP1B, and PP2A, to inhibit their activity and promote activation of the PI3K/Akt survival pathway (Lee et al. 2002, Rao & Clayton 2002, Salmeen et al. 2003).”

“stabilization of HIF-1α protein during hypoxia (Lee et al. 2016).”

“Furthermore, the oncogenic activation of Akt can increase ROS production to further promote cancer cell survival and proliferation (Behrend et al. 2003, Los et al. 2009).”

“Additionally, buthionine sulfoximine (BSO), an inhibitor of glutamate cysteine ligase (GCL), the enzyme required for GSH synthesis, depletes GSH and exhibits anticancer activity (Andringa et al. 2006, Bailey et al. 1997, Griffith & Meister 1979).”

“In agreement with these results, a high-throughput chemical screen to identify inhibitors of the growth of EGFR- or Kras-driven non-small-cell lung cancer cells identified the small SOD1 inhibitor molecule LCS-1 (Somwar et al. 2011).”

“ROS have been shown to confer anoikis resistance to cancer cells through the oxidation and activation of Src, leading to constitutive, ligand-independent EGFR activation and prosurvival signaling (Giannoni et al. 2009).”

“When ROS levels are too high, cell cycle arrest, senescence, and cancer cell death can occur (Ichijo et al. 1997, Moon et al. 2010).”

“ROS-mediated activation of the JNK and p38 signaling pathways can also induce cell cycle arrest, preventing cancer cell growth and division (Ambrosino & Nebreda 2001, Thornton & Rincon 2009, Wagner & Nebreda 2009).”

“2011:792639 St. Clair DK, Wan XS, Oberley TD, Muse KE, St. Clair WH. 1992.”

“Enhanced ROS scavenging due to NRF2-mediated gene expression in cancer cells likely maintains ROS homeostasis by preventing ROS-mediated activation of the death-inducing JNK/p38 pathways and irreversible oxidative damage.”

“Mitochondrial transcription factor A heterozygous mice, which have less mitochondrial DNA and elevated mROS levels, displayed enhanced tumorigenesis in an APCMin/+ mouse model of intestinal cancer, further implicating mROS in tumorigenesis (Woo et al. 2012).”

“LCS-1 impaired the integrity of the mitochondria in breast cancer cell lines, but not in nontumorigenic cell lines, suggesting SOD1 inhibition as a potential therapeutic approach for breast cancer (Papa et al. 2014).”

“Compounds that rapidly conjugate with GSH and deplete the GSH pool promote oxidative stress–induced cancer cell death (Dvorakova et al. 2000, Xu & Thornalley 2001).”

“Moreover, through the induction of the metabolic gene TIGAR, p53 can control antioxidant function (Bensaad et al. 2006; Cheung et al. 2012, 2013).”

“Thus, perturbing these ROS-mitigating pathways may be a viable therapeutic approach for suppressing cancer cell proliferation and metastasis (Adhikary et al. 2010, Wu et al. 2010).”

“ROS also oxidize and inactivate MAPK phosphatases, inducing growth factor receptor activation and MAPK/ERK pro-proliferative signaling (Seth & Rudolph 2006, Son et al. 2011).”

“HIF-α stabilization through a ROS-dependent mechanism has been shown to promote the tumorigenesis of certain cancer cells (Gao et al. 2007, Horak et al. 2010, Ma et al. 2009).”

“Therefore, targeting specific, NRF2-regulated, NADPH-producing metabolic pathways may be a more effective approach to anticancer therapeutics (DeNicola et al. 2015, Fan et al. 2014, Labuschagne et al. 2014, Lewis et al. 2014).”

“This therapeutic approach may be particularly beneficial for targeting cancer stem cells (CSCs), a highly tumorigenic subpopulation of cancer cells often resistant to chemotherapy and ionizing radiation (Meacham & Morrison 2013, Yang et al. 2016).”

“The combination of 2DG with BSO had a similar effect on human breast cancer cells (Andringa et al. 2006).”

“Perhaps a similar mechanism occurs in the mitochondria, whereby mROS activate intermembrane space–localized Lyn, a Src family member, and the Syk kinase pathway to control cellular processes, such as transcription, metabolism, and cell cycle regulation (Patterson et al. 2015).”

“The exact role of ROS may depend on the stage and type of cancer (85).”