Mitochondrial dysfunction suppresses p53 expression via calcium-mediated nuclear factor-kB signaling in HCT116 human colorectal carcinoma cells

Lee, Young-Kyoung; Yi, Eui-Yeun; Park, Shi-Young; Jang, Won‐Jun; Han, Yu-Seon; Jegal, Myeong-Eun; Kim, Yung-Jin

doi:10.5483/bmbrep.2018.51.6.232

Cited by 6 publications

(5 citation statements)

References 34 publications

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“…Subsequently, these mtDNA mutations could be further fixed in CC cells during the next cell divisions and impair mitochondrial functions and/or accelerate ROS production. Dysfunctional mitochondria could further lead to decreased p53 expression, as was shown by Lee et al, 30 and thus contribute to further mtDNA mutagenesis.…”

Section: Discussionmentioning

confidence: 79%

TP53 somatic mutations are associated with somatic mitogenome substitutions but not indels in colorectal cancer cells

Skonieczna

Jawień

Marszałek

et al. 2019

The Journal of Gene Medicine

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Background p53 is a tumour suppressor protein that is involved in many cancer‐related processes. Growing evidence suggests that p53 also plays an important role in mitochondrial (mtDNA) maintenance. Somatic mitogenome mutations are frequently observed in colorectal cancer (CC) cells. Thus, it was important to determine whether somatic mtDNA changes are associated with TP53 mutational status. Methods In the present study, we analysed the TP53 gene in 67 CC patients, for whom mitogenome haplotypes were previously described. In total, 134 TP53 sequences (of cancer and matched normal specimens) were determined using the dideoxy method. Results Nine hereditary polymorphisms in the TP53 gene were detected in normal colon cells. None of them (neither alleles, nor genotypes) was associated with somatic mitogenome mutations in CC cells. Moreover, 42 somatic TP53 mutations were found in approximately 36% of CC tissues. These somatic changes were significantly more frequent in CC cells with somatic mtDNA mutations (p = 0.0069). Furthermore, we show that only mitochondrial somatic substitutions (p = 0.0017), but not indels (p > 0.05), were associated with somatic TP53 mutations. Conclusions The results of the present study suggest that changes in TP53 may modify p53 properties, which may result in the accumulation of somatic substitutions in CC mitogenomes.

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Section: Discussionmentioning

confidence: 79%

TP53 somatic mutations are associated with somatic mitogenome substitutions but not indels in colorectal cancer cells

Skonieczna

Jawień

Marszałek

et al. 2019

The Journal of Gene Medicine

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“…In macrophages, LPS can elevate intracellular calcium concentration [Ca ++ ] i , resulting in increased NFκB phosphorylation and nuclear translocation ( 25 , 26 , 32 ). In support of this, our study clearly showed that treatment of macrophages with PN-101 abolished LPS-induced [Ca ++ ] i elevation ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Human umbilical cord mesenchymal stem cell-derived mitochondria (PN-101) attenuate LPS-induced inflammatory responses by inhibiting NFκB signaling pathway

Yu¹,

Kim²,

Kim³

et al. 2022

BMB Rep

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Inflammation is one of the body’s natural responses to injury and illness as part of the healing process. However, persistent inflammation can lead to chronic inflammatory diseases and multi-organ failure. Altered mitochondrial function has been implicated in several acute and chronic inflammatory diseases by inducing an abnormal inflammatory response. Therefore, treating inflammatory diseases by recovering mitochondrial function may be a potential therapeutic approach. Recently, mitochondrial transplantation has been proven to be beneficial in hyperinflammatory animal models. However, it is unclear how mitochondrial transplantation attenuates inflammatory responses induced by external stimuli. Here, we isolated mitochondria from umbilical cord-derived mesenchymal stem cells, referred as to PN-101. We found that PN-101 could signifi-cantly reduce LPS-induced mortality in mice. In addition, in phorbol 12-myristate 13-acetate (PMA)-treated THP-1 macrophages, PN-101 attenuated LPS-induced increase production of pro-inflammatory cytokines. Furthermore, the anti-inflammatory effect of PN-101 was mediated by blockade of phosphorylation, nuclear translocation, and trans-activity of NFκB. Taken together, our results demonstrate that PN-101 has therapeutic potential to attenuate pathological inflammatory responses.

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“…Activation of NF-κB frequently occurs in tumors, especially in those with drug or radiotherapy resistance (19)(20)(21). The dimeric NF-κB complexes are localized to the cytosol through interaction with Inhibitor of NF-κB (IκBα).…”

Section: Discussionmentioning

confidence: 99%

TIGAR Enhanced Free Ca2+ Concentration in Hepatocellular Carcinoma Cells to Accelerate the Sustained Proliferation and Drug Resistance

Xie

Sui

Feng

et al. 2021

Preprint

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Background: To study the role of TP53-induced glycolysis and apoptosis regulator (TIGAR) in hepatocellular carcinoma (HCC) and drug resistance.Methods: HCC cells (HepG2 and SMMC7721) were used in this study. Fura 2-AM was used to assess cytosolic free Ca2+ concentrations ([Ca2+]i) within the two HCC cell lines. Nimodipine (NMDP), a Ca2+ antagonist, was used to reduce cytosolic [Ca2+]i level. Proliferation of HCC was measured using cell counting kit-8 (CCK-8). The roles of TIGAR and Ca2+ in drug resistance of HCC cells were assessed using epirubicin (Epi), 5-fluorouracil (5-FU), or cisplatinum (DDP).Results: Knockdown of TIGAR significantly suppressed cell viability, reduced [Ca2+]i, restrained protein expression of Ca2+-activated cysteine proteinases (Calpain1 and 2), as well as blocked the activation of nuclear factor kappa B (NF-κB) through an increase of cytoplasmic NF-κB and reduction of nuclear NF-κB. However, overexpression of TIGAR (oeTIGAR) resulted in the opposite. Evidence also shows that oeTIGAR suppressed the sensitivity of HCC to Epi, which was retarded by NMDP as an additional treatment. TIGAR interference could enhance the sensitivity of HCCs with high TIGAR expression to drugs.Conclusions: TIGAR promoted HCC progression and induced drug resistance, and the mechanism involved was [Ca2+]i-mediated activation of Calpain 1 and 2 and NF-κB signaling.

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Mitochondrial dysfunction suppresses p53 expression via calcium-mediated nuclear factor-kB signaling in HCT116 human colorectal carcinoma cells

Cited by 6 publications

References 34 publications

TP53 somatic mutations are associated with somatic mitogenome substitutions but not indels in colorectal cancer cells

TP53 somatic mutations are associated with somatic mitogenome substitutions but not indels in colorectal cancer cells

Human umbilical cord mesenchymal stem cell-derived mitochondria (PN-101) attenuate LPS-induced inflammatory responses by inhibiting NFκB signaling pathway

TIGAR Enhanced Free Ca2+ Concentration in Hepatocellular Carcinoma Cells to Accelerate the Sustained Proliferation and Drug Resistance

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