Increased cytochrome c correlates with poor survival in aggressive lymphoma

Wilkinson, Sarah T.; Johnson, David; Tardif, Heather L.; Tome, Margaret E.; Briehl, Margaret M.

doi:10.3892/ol_00000040

Cited by 9 publications

(11 citation statements)

References 13 publications

(25 reference statements)

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“…High levels of HK2 are required for tumor initiation 46 , 47 . Cytochrome-c was found to be associated with drug resistance in thymic lymphoma cells 48 . We therefore performed screening of lymphoma tissue microarrays (Biomax) to validate the expression of metabolic markers GLUT1 , Cyt-C and HK2 in human DLBCL patient samples and explore their prognostic importance.…”

Section: Resultsmentioning

confidence: 99%

Role of hypoxia in Diffuse Large B-cell Lymphoma: Metabolic repression and selective translation of HK2 facilitates development of DLBCL

Bhalla

Jaber

et al. 2018

Sci Rep

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Published molecular profiling studies in patients with lymphoma suggested the influence of hypoxia inducible factor-1 alpha (HIF1α) targets in prognosis of DLBCL. Yet, the role of hypoxia in hematological malignancies remains unclear. We observed that activation of HIF1α resulted in global translation repression during hypoxic stress in DLBCL. Protein translation efficiency as measured using 35S-labeled methionine incorporation revealed a ≥50% reduction in translation upon activation of HIF1α. Importantly, translation was not completely inhibited and expression of clinically correlated hypoxia targets such as GLUT1, HK2, and CYT-C was found to be refractory to translational repression under hypoxia in DLBCL cells. Notably, hypoxic induction of these genes was not observed in normal primary B-cells. Translational repression was coupled with a decrease in mitochondrial function. Screening of primary DLBCL patient samples revealed that expression of HK2, which encodes for the enzyme hexokinase 2, was significantly correlated with DLBCL phenotype. Genetic knockdown studies demonstrated that HK2 is required for promoting growth of DLBCL under hypoxic stress. Altogether, our findings provide strong support for the direct contribution of HK2 in B-cell lymphoma development and suggest that HK2 is a key metabolic driver of the DLBCL phenotype.

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Section: Resultsmentioning

confidence: 99%

Role of hypoxia in Diffuse Large B-cell Lymphoma: Metabolic repression and selective translation of HK2 facilitates development of DLBCL

Bhalla

Jaber

et al. 2018

Sci Rep

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“…Differences in levels of pro- or anti-apoptotic BCL-2 family members do not explain the resistance of the variant cells’ mitochondria to the intrinsic pathway to apoptosis [46]. Increased cytochrome c levels are present in mitochondria from the variants [45] and this may play a role.…”

Section: Manipulating Redox Homeostasis Results In More Aggressive Camentioning

confidence: 99%

“…Cell lines derived from tumors with the OxPhos signature have enhanced mitochondrial energy transduction, greater flux through the TCA cycle and increased glutathione levels compared to non-OxPhos DLBCLs [7]. In light of these findings and the mitochondrial changes seen in the WEHI7.2 variants, we compared the expression of cytochrome c with response to therapy in different lymphoma subtypes [45]. No association is seen for patients with follicular lymphoma, an indolent form of the disease.…”

Section: Treatment-refractory Lymphomas Are Metabolic Opportunistsmentioning

confidence: 99%

Mitochondria and redox homoeostasis as chemotherapeutic targets

Briehl

Tome

Wilkinson

et al. 2014

Biochemical Society Transactions

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Characteristics of cancer cells include a more oxidized redox environment, metabolic reprogramming, and apoptosis resistance. Our studies with a lymphoma model have explored connections between the cellular redox environment and cancer cell phenotypes. Alterations seen in lymphoma cells made resistant to oxidative stress include: a more oxidized redox environment despite increased expression of antioxidant enzymes, enhanced net tumor growth, metabolic changes involving the mitochondria, and resistance to the mitochondrial pathway to apoptosis. Of particular importance, the cells show cross-resistance to multiple chemotherapeutic agents used to treat aggressive lymphomas. Analyses of clinical and tumor data reveal the worst prognosis when patients’ lymphomas have gene expression patterns consistent with the most oxidized redox environment. Lymphomas from patients with the worst survival outcomes express increased levels of proteins involved in oxidative phosphorylation, including cytochrome c. This is consistent with these cells functioning as metabolic opportunists. Using lymphoma cell models and primary lymphoma cultures, we observed enhanced killing using genetic and drug approaches which further oxidize the cellular redox environment. These approaches include increased expression of SOD2, treatment with a manganoporphyrin that oxidizes the glutathione redox couple, or treatment with a copper chelator that inhibits SOD1 and leads to peroxynitrite-dependent cell death. The latter approach effectively kills lymphoma cells that overexpress the anti-apoptotic protein BCL-2. Given the central role of mitochondria in redox homeostasis, metabolism and the intrinsic pathway to apoptosis, our studies support the development of new anti-cancer drugs to target this organelle.

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“…CAT2, CAT38 and 200R cells all have elevated cytochrome c compared to the control cells [44]. Increased cytochrome c could contribute to the ability to maintain mitochondrial function under stress conditions.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial Adaptations to Oxidative Stress Confer Resistance to Apoptosis in Lymphoma Cells

Wilkinson

Tome

Briehl

2012

IJMS

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Acquired resistance to drugs commonly used for lymphoma treatment poses a significant barrier to improving lymphoma patient survival. Previous work with a lymphoma tissue culture model indicates that selection for resistance to oxidative stress confers resistance to chemotherapy-induced apoptosis. This suggests that adaptation to chronic oxidative stress can contribute to chemoresistance seen in lymphoma patients. Oxidative stress-resistant WEHI7.2 cell variants in a lymphoma tissue culture model exhibit a range of apoptosis sensitivities. We exploited this phenotype to test for mitochondrial changes affecting sensitivity to apoptosis in cells made resistant to oxidative stress. We identified impaired release of cytochrome c, and the intermembrane proteins adenylate kinase 2 and Smac/DIABLO, indicating inhibition of the pathway leading to permeabilization of the outer mitochondrial membrane. Blunting of a glucocorticoid-induced signal and intrinsic mitochondrial resistance to cytochrome c release contributed to both points of resistance. The level of Bcl-2 family members or a difference in Bim induction were not contributing factors. The extent of cardiolipin oxidation following dexamethasone treatment, however, did correlate with apoptosis resistance. The differences found in the variants were all proportionate to the degree of resistance to glucocorticoid treatment. We conclude that tolerance to oxidative stress leads to mitochondrial changes that confer resistance to apoptosis.

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Increased cytochrome c correlates with poor survival in aggressive lymphoma

Cited by 9 publications

References 13 publications

Role of hypoxia in Diffuse Large B-cell Lymphoma: Metabolic repression and selective translation of HK2 facilitates development of DLBCL

Role of hypoxia in Diffuse Large B-cell Lymphoma: Metabolic repression and selective translation of HK2 facilitates development of DLBCL

Mitochondria and redox homoeostasis as chemotherapeutic targets

Mitochondrial Adaptations to Oxidative Stress Confer Resistance to Apoptosis in Lymphoma Cells

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