Oroxylin A modulates mitochondrial function and apoptosis in human colon cancer cells by inducing mitochondrial translocation of wild-type p53

Qiao, Chun‐Feng; Lu, Na; Zhou, Yuxin; Ni, Ting; Dai, Yuanyuan; Li, Zhiyu; Guo, Qinglong; Wei, Libin

doi:10.18632/oncotarget.7927

Cited by 21 publications

(9 citation statements)

References 27 publications

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“…Cancer cells can be severely starved from nutrients and oxygen in an ischemic tumor microenvironment due to poor tumor vascularization (Gorrini et al, 2013; Trachootham et al, 2009), making cancer an excellent model to study nutrient regulation of redox homeostasis in mammals. As reported previously (Qiao et al, 2016; Semenza, 2000), deprivation of nutrients and oxygen, an ischemic condition, leads to rapid inhibition of mTORC1 signaling as shown by the decreased phosphorylation of mTORC1 effectors S6K1 and S6, but activation of AMPK and HIF1α, two hypoxic markers (Figure 6A). Similarly to the yeast results, human SOD1 but not SOD2 becomes rapidly activated (Figure 6A).…”

Section: Resultssupporting

confidence: 82%

SOD1 Phosphorylation by mTORC1 Couples Nutrient Sensing and Redox Regulation

et al. 2018

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Nutrients are not only organic compounds fueling bioenergetics and biosynthesis, but also key chemical signals controlling growth and metabolism. Nutrients enormously impact the production of reactive oxygen species (ROS), which play essential roles in normal physiology and diseases. How nutrient signaling is integrated with redox regulation is an interesting, but not fully understood, question. Herein, we report that superoxide dismutase 1 (SOD1) is a conserved component of the mechanistic target of rapamycin complex 1 (mTORC1) nutrient signaling. mTORC1 regulates SOD1 activity through reversible phosphorylation at S39 in yeast and T40 in humans in response to nutrients, which moderates ROS level and prevents oxidative DNA damage. We further show that SOD1 activation enhances cancer cell survival and tumor formation in the ischemic tumor microenvironment and protects against the chemotherapeutic agent cisplatin. Collectively, these findings identify a conserved mechanism by which eukaryotes dynamically regulate redox homeostasis in response to changing nutrient conditions.

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Section: Resultssupporting

confidence: 82%

SOD1 Phosphorylation by mTORC1 Couples Nutrient Sensing and Redox Regulation

et al. 2018

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“…In previous studies, we found that OA induced apoptosis of HCT116 cells. 23 Here, HCT116 cells were prestimulated with 50 μ M PA. The results of MTT assay and Ki67 staining showed that OA inhibited the growth of HCT116 cells with the IC50 value of 38.7 μ M under hypoxia ( Figures 3a and b ).…”

Section: Resultsmentioning

confidence: 99%

Oroxylin A suppresses the development and growth of colorectal cancer through reprogram of HIF1α-modulated fatty acid metabolism

Dai

et al. 2017

Cell Death Dis

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The occurrence and progress of colon cancer are closely associated with obesity. Therefore, the lipid metabolism, especially fatty acid metabolism, is a significant section of energy homeostasis in colon cancer cells, and it affects many important cellular processes. Oroxylin A is one of the main bioactive flavonoids of Scutellariae radix, which has a strong anticancer effect but low toxicity to normal tissue. In previous studies, we have proved that oroxylin A reprogrammes metabolism of cancer cells by inhibiting glycolysis. Here, we further investigated the metabolism-modulating effects of oroxylin A on the fatty acid metabolism in colon cancer cells under hypoxia. We found that HIF1α upregulated adipophilin, fatty acid synthase and sterol regulatory element-binding protein 1, and downregulated carnitine palmitoyltransferase 1 (CPT1), resulting in the promoted lipid uptake and transport, increased de novo fatty acid synthesis and suppressed fatty acid oxidation. Oroxylin A inactivated HIF1α and reprogrammed fatty acid metabolism of HCT116 cells, decreasing intracellular fatty acid level and enhancing fatty acid oxidation. Furthermore, the rapid decrease of fatty acid level caused by oroxylin A inhibited the nuclear translocation of β-cantenin and inactivated the Wnt pathway, arousing cell cycle arrest in G2/M phase. In vivo studies demonstrated that high-fat diet increased the incidence of colon cancer and accelerated tumor development. Importantly, besides the growth inhibitory effects on colon cancer xenograft, oroxylin A prevented carcinogenesis and delayed progress of primary colon cancer as well. Our studies enriched the metabolic regulatory mechanism of oroxylin A, and suggested that oroxylin A was a potent candidate for the treatment and prevention of colorectal cancer.

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“…p53 is an important aging factor that controls cellular senescence [ 40 , 41 ]. p53 regulates mitochondrial functions [ 42 , 43 ] and redox homeostasis in part through the control of SOD2 expression [ 33 , 34 ]. p53 is an important tumor suppressor in human cancer and TP53 is estimated to be mutated in 30-50% of human liver cancer according to the cBioPortal ( http://www.cbioportal.org ).…”

Section: Discussionmentioning

confidence: 99%

Reduced SOD2 expression is associated with mortality of hepatocellular carcinoma patients in a mutant p53-dependent manner

Ren

Chen

et al. 2016

Aging

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The development and progression of hepatocellular carcinoma (HCC) is accompanied with persistent oxidative stress, but the molecular basis is not well defined. Superoxide dismutase 2 (SOD2) is an important mitochondrial antioxidant and a key aging factor. Here we investigated the expression and clinical significance of SOD2 in a large cohort of HBV-positive HCC tumors. Both SOD2 mRNA and protein are reduced in human primary HCCs compared with matching liver tissues. Consistently, the SOD2 DNA copy numbers are decreased in HCCs, providing a genetic basis for the decrease in SOD2 mRNA expression. Reduced SOD2 expression in HCCs is correlated with older age, larger tumor size, multiple tumor nodules and tumor emboli, and cancer recurrence. Moreover, low SOD2 expression is strongly associated with poor overall survival (OS) and recurrence-free survival (RFS). Univariate and multivariate Cox regression analyses indicates that SOD2 is an independent prognostic predictor for OS and RFS. Intriguingly, reduced SOD2 mRNA is strongly associated with poor survival in a separate cohort of HCC patients carrying mutant p53. Altogether, our results provide clinical evidence for the importance of SOD2 in tumor progression and mortality, and the close relationship of SOD2 and p53 in HCC.

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Oroxylin A modulates mitochondrial function and apoptosis in human colon cancer cells by inducing mitochondrial translocation of wild-type p53

Cited by 21 publications

References 27 publications

SOD1 Phosphorylation by mTORC1 Couples Nutrient Sensing and Redox Regulation

SOD1 Phosphorylation by mTORC1 Couples Nutrient Sensing and Redox Regulation

Oroxylin A suppresses the development and growth of colorectal cancer through reprogram of HIF1α-modulated fatty acid metabolism

Reduced SOD2 expression is associated with mortality of hepatocellular carcinoma patients in a mutant p53-dependent manner

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