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MicroRNA-661 modulates redox and metabolic homeostasis in colon cancer.

ABSTRACT: Cancer cell survival and metastasis are dependent on metabolic reprogramming that is capable of increasing resistance to oxidative and energetic stress. Targeting these two processes can be crucial for cancer progression. Herein, we describe the role of microRNA-661 (miR661) as epigenetic regulator of colon cancer (CC) cell metabolism. MicroR661 induces a global increase in reactive oxygen species, specifically in mitochondrial superoxide anions, which appears to be mediated by decreased carbohydrate metabolism and pentose phosphate pathway, and by a higher dependency on mitochondrial respiration. MicroR661 overexpression in non-metastatic human CC cells induces an epithelial-to-mesenchymal transition phenotype, and a reduced tolerance to metabolic stress. This seems to be a general effect of miR661 in CC, since metastatic CC cell metabolism is also compromised upon miR661 overexpression. We propose hexose-6-phosphate dehydrogenase and pyruvate kinase M2 as two key players related to the observed metabolic reprogramming. Finally, the clinical relevance of miR661 expression levels in stage-II and III CC patients is discussed. In conclusion, we propose miR661 as a potential modulator of redox and metabolic homeostasis in CC.

SUBMITTER: Gomez de Cedron M

PROVIDER: S-EPMC5709620 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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MicroRNA-661 modulates redox and metabolic homeostasis in colon cancer.

Gómez de Cedrón Marta M Acín Pérez Rebeca R Sánchez-Martínez Ruth R Molina Susana S Herranz Jesús J Feliu Jaime J Reglero Guillermo G Enríquez Jose Antonio JA Ramírez de Molina Ana A

Molecular oncology 20171106 12

Cancer cell survival and metastasis are dependent on metabolic reprogramming that is capable of increasing resistance to oxidative and energetic stress. Targeting these two processes can be crucial for cancer progression. Herein, we describe the role of microRNA-661 (miR661) as epigenetic regulator of colon cancer (CC) cell metabolism. MicroR661 induces a global increase in reactive oxygen species, specifically in mitochondrial superoxide anions, which appears to be mediated by decreased carbohy ...[more]

PMID: 28981199

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Project description:Modest levels of reactive oxygen species (ROS) are necessary for intracellular signaling, cell division, and enzyme activation. These ROS are later eliminated by the body's antioxidant defense system. High amounts of ROS cause carcinogenesis by altering the signaling pathways associated with metabolism, proliferation, metastasis, and cell survival. Cancer cells exhibit enhanced ATP production and high ROS levels, which allow them to maintain elevated proliferation through metabolic reprograming. In order to prevent further ROS generation, cancer cells rely on more glycolysis to produce ATP and on the pentose phosphate pathway to provide NADPH. Pro-oxidant therapy can induce more ROS generation beyond the physiologic thresholds in cancer cells. Alternatively, antioxidant therapy can protect normal cells by activating cell survival signaling cascades, such as the nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway, in response to radio- and chemotherapeutic drugs. Nrf2 is a key regulator that protects cells from oxidative stress. Under normal conditions, Nrf2 is tightly bound to Keap1 and is ubiquitinated and degraded by the proteasome. However, under oxidative stress, or when treated with Nrf2 activators, Nrf2 is liberated from the Nrf2-Keap1 complex, translocated into the nucleus, and bound to the antioxidant response element in association with other factors. This cascade results in the expression of detoxifying enzymes, including NADH-quinone oxidoreductase 1 (NQO1) and heme oxygenase 1. NQO1 and cytochrome b5 reductase can neutralize ROS in the plasma membrane and induce a high NAD+/NADH ratio, which then activates SIRT1 and mitochondrial bioenergetics. NQO1 can also stabilize the tumor suppressor p53. Given their roles in cancer pathogenesis, redox homeostasis and the metabolic shift from glycolysis to oxidative phosphorylation (through activation of Nrf2 and NQO1) seem to be good targets for cancer therapy. Therefore, Nrf2 modulation and NQO1 stimulation could be important therapeutic targets for cancer prevention and treatment.

Project description:Manganese (Mn) is an essential trace element that is supplemented in microbial media with varying benefits across species and growth conditions. We found that growth of Lactococcus cremoris was unaffected by manganese omission from the growth medium. The main proteome adaptation to manganese omission involved increased manganese transporter production (up to 2,000-fold), while the remaining 10 significant proteome changes were between 1.4- and 4-fold. Further investigation in translationally blocked (TB), nongrowing cells showed that Mn supplementation (20 μM) led to approximately 1.5 X faster acidification compared with Mn-free conditions. However, this faster acidification stagnated within 24 h, likely due to draining of intracellular NADH that coincides with substantial loss of culturability. Conversely, without manganese, nongrowing cells persisted to acidify for weeks, albeit at a reduced rate, but maintaining redox balance and culturability. Strikingly, despite being unculturable, α-keto acid-derived aldehydes continued to accumulate in cells incubated in the presence of manganese, whereas without manganese cells predominantly formed the corresponding alcohols. This is most likely reflecting NADH availability for the alcohol dehydrogenase-catalyzed conversion. Overall, manganese influences the lactococcal acidification rate, and flavor formation capacity in a redox dependent manner. These are important industrial traits especially during cheese ripening, where cells are in a non-growing, often unculturable state. IMPORTANCE In nature as well as in various biotechnology applications, microorganisms are often in a nongrowing state and their metabolic persistence determines cell survival and functionality. Industrial examples are dairy fermentations where bacteria remain active during the ripening phases that can take up to months and even years. Here we investigated environmental factors that can influence lactococcal metabolic persistence throughout such prolonged periods. We found that in the absence of manganese, acidification of nongrowing cells remained active for weeks while in the presence of manganese it stopped within 1 day. The latter coincided with the accumulation of amino acid derived volatile metabolites. Based on metabolic conversions, proteome analysis, and a reporter assay, we demonstrated that the manganese elicited effects were NADH dependent. Overall the results show the effect of environmental modulation on prolonged cell-based catalysis, which is highly relevant to non-growing cells in nature and biotechnological applications.

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MicroRNA-661 modulates redox and metabolic homeostasis in colon cancer.

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MicroRNA-661 modulates redox and metabolic homeostasis in colon cancer.

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