Mitochondrial Complex I decrease is responsible for bioenergetic dysfunction in K-ras transformed cells

Baracca, Alessandra; Chiaradonna, Ferdinando; Sgarbi, Gianluca; Alberghina, Lilia; Lenaz, Giorgio

doi:10.1016/j.bbabio.2009.11.006

Cited by 123 publications

(84 citation statements)

References 55 publications

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“…mtDNA mutations per se are not known to cause transformation (40), but may contribute to cancer progression, as seen in lung carcinoma with EGFR mutations (41) and in oncocytic tumors with loss of complex I function (14,42). Furthermore, oncogene activity (e.g., K-Ras transformation) can decrease mitochondrial complex I activity (43), which may support a malignant phenotype (44). Our results revealed a cause-and-effect relationship between complex I function and breast cancer progression.…”

Section: Discussionmentioning

confidence: 69%

Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression

Santidrián

Matsuno‐Yagi²,

Ritland³

et al. 2013

J. Clin. Invest.

337

273

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IntroductionDespite advances in clinical therapy, metastasis is still the leading cause of death in breast cancer patients (1). A clearer understanding of molecular mechanisms that drive metastasis will help to develop more effective therapies (2). Our present study focused on metabolism as an essential driver of tumor growth and metastasis, potentially common to all breast cancer types. Normal cells primarily use mitochondrial oxidative phosphorylation (OXPHOS) for energy production, whereas cancer cells depend on aerobic glycolysis (the Warburg effect) to generate energy and glycolytic intermediates for enhanced growth (3, 4). Tumor cells also generate high levels of reduced forms of NAD + , NADH, and NADPH as important cofactors and redox components (4, 5). These altered metabolic activities can be linked to mitochondrial dysfunction that inhibits OXPHOS, increases ROS, promotes uncontrolled growth, and causes DNA damage that further supports a metastatic phenotype (6, 7). Mitochondrial dysfunctions can be caused by mutations in mitochondrial DNA (mtDNA) or nuclear genes encoding mitochondrial proteins (6,8) that are essential for the respiratory chain/OXPHOS system. Due to the lack of protective histones and limited DNA repair (8), mtDNA mutations occur at high rates and were found in tumors including breast cancer (6,(9)(10)(11)(12)(13)(14), which suggests that defects in OXPHOS might contribute to tumorigenesis.By combining the nuclear genome of a recipient cell with the mitochondrial genome of a donor cell using cybrid technology, mitochondria from the triple-negative aggressive breast cancer cell lines MDA-MB-435 (15) and MDA-MB-231 facilitated tumor progression and metastasis in nonmetastatic tumor cells (7, 10). The donor cell lines harbor mtDNA mutations in tRNAs, in the

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Section: Discussionmentioning

confidence: 69%

Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression

Santidrián

Matsuno‐Yagi²,

Ritland³

et al. 2013

J. Clin. Invest.

337

273

View full text Add to dashboard Cite

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“…This result is in keeping with previous studies showing that K-ras-transformed cells have defective mitochondria 19 and, more specifically, that the reduction in respiration observed is due to a decrease in complex I activity. 24 …”

Section: Glucose Limitation Sensitizes Transformed Cells To Growth Immentioning

confidence: 99%

Nutritional Limitation Sensitizes Mammalian Cells to GSK-3β Inhibitors and Leads to Growth Impairment

Candia

Minopoli

Verga

et al. 2011

The American Journal of Pathology

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The serine/threonine kinase GSK-3␤ was initially described as a key enzyme involved in glucose metabolism, but it is now known to regulate a wide range of biological processes, including proliferation and apoptosis. We previously reported a transformation-dependent cell death induced by glucose limitation in K-ras-transformed NIH3T3. To address the mechanism of this phenomenon, we analyzed GSK-3␤ regulation in these cells in conditions of high versus low glucose availability. We found that glucose depletion caused a marked inhibition of GSK-3␤ through posttranslational mechanisms and that this inhibition was much less pronounced in normal cells. Further inhibition of GSK-3␤ with lithium chloride, combined with glucose shortage, caused specific activation of AMPactivated protein kinase and significant suppression of proliferation in transformed but not normal cells. The cooperative effect of lithium and low glucose availability on cell growth did not seem to depend exclusively on ras pathway activation because two human cell lines, A549 and MDA-MB-231, both harboring an activated ras gene, showed very different sensitivity to lithium. These findings thus provide a rationale to further analyze the biochemical bases for combined glucose deprivation and GSK-3␤ inhibition as a new approach to control transformed cell growth.

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“…Cells were cultured in six-well microplates and washed once before the addition of 0.1 mM 2-deoxy-D- [2, H]glucose (1 Ci) in Krebs-Ringer's phosphate buffer for 5 min at 37°C. The assay was terminated by the rapid removal of assay buffer followed by four rapid washes with 1 ml of ice-cold buffer containing 500 M phloretin.…”

Section: Cell Culture and Cell Lines Ksr1mentioning

confidence: 99%

Kinase Suppressor of Ras 1 (KSR1) Regulates PGC1α and Estrogen-Related Receptor α To Promote Oncogenic Ras-Dependent Anchorage-Independent Growth

Fisher

Das

Kortum

et al. 2011

Molecular and Cellular Biology

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Kinase suppressor of ras 1 (KSR1) is a molecular scaffold of the Raf/MEK/extracellular signal-regulated kinase (ERK) cascade that enhances oncogenic Ras signaling. Here we show KSR1-dependent, but ERKindependent, regulation of metabolic capacity is mediated through the expression of peroxisome proliferatoractivated receptor gamma coactivator 1␣ (PGC1␣) and estrogen-related receptor ␣ (ERR␣). This KSR1-regulated pathway is essential for the transformation of cells by oncogenic Ras. In mouse embryo fibroblasts (MEFs) expressing H-Ras V12 , ectopic PGC1␣ was sufficient to rescue ERR␣ expression, metabolic capacity, and anchorage-independent growth in the absence of KSR1. The ability of PGC1␣ to promote anchorageindependent growth required interaction with ERR␣, and treatment with an inhibitor of ERR␣ impeded anchorage-independent growth. In contrast to PGC1␣, the expression of constitutively active ERR␣ (CA-ERR␣) was sufficient to enhance metabolic capacity but not anchorage-independent growth in the absence of KSR1. These data reveal KSR1-dependent control of PGC1␣-and ERR␣-dependent pathways that are necessary and sufficient for signaling by oncogenic H-Ras V12 to regulate metabolism and anchorage-independent growth, providing novel targets for therapeutic intervention.

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Mitochondrial Complex I decrease is responsible for bioenergetic dysfunction in K-ras transformed cells

Cited by 123 publications

References 55 publications

Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression

Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression

Nutritional Limitation Sensitizes Mammalian Cells to GSK-3β Inhibitors and Leads to Growth Impairment

Kinase Suppressor of Ras 1 (KSR1) Regulates PGC1α and Estrogen-Related Receptor α To Promote Oncogenic Ras-Dependent Anchorage-Independent Growth

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