Mitochondria: promising organelle targets for cancer diagnosis and treatment

Hou, Xia; Wang, Huai-Song; Mugaka, Benson Peter; Yang, Gongjun; Ding, Ya

doi:10.1039/c8bm00673c

Cited by 66 publications

(54 citation statements)

References 89 publications

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“…Mitochondria have been reported to be involved in different programmed cell death processes, including apoptosis and mitophagy [113,114]. Recently, it was reported that mitochondria are also involved in ferroptosis [115].…”

Section: Wild-type P53 Inhibits Ferroptosismentioning

confidence: 99%

The Regulation of Ferroptosis by Tumor Suppressor p53 and its Pathway

Liu

Zhang

Wang

et al. 2020

IJMS

134

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Tumor suppressor p53 plays a key role in tumor suppression. In addition to tumor suppression, p53 is also involved in many other biological and pathological processes, such as immune response, maternal reproduction, tissue ischemia/reperfusion injuries and neurodegenerative diseases. While it has been widely accepted that the role of p53 in regulation of cell cycle arrest, senescence and apoptosis contributes greatly to the function of p53 in tumor suppression, emerging evidence has implicated that p53 also exerts its tumor suppressive function through regulation of many other cellular processes, such as metabolism, anti-oxidant defense and ferroptosis. Ferroptosis is a unique iron-dependent form of programmed cell death driven by lipid peroxidation in cells. Ferroptosis has been reported to be involved in cancer, tissue ischemia/reperfusion injuries and neurodegenerative diseases. Recent studies have shown that ferroptosis can be regulated by p53 and its signaling pathway as well as tumor-associated mutant p53. Interestingly, the regulation of ferroptosis by p53 appears to be highly context-dependent. In this review, we summarize recent advances in the regulation of ferroptosis by p53 and its signaling pathway. Further elucidation of the role and molecular mechanism of p53 in ferroptosis regulation will yield new therapeutic strategies for cancer and other diseases, including neurodegenerative diseases and tissue ischemia/reperfusion injuries.

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Section: Wild-type P53 Inhibits Ferroptosismentioning

confidence: 99%

The Regulation of Ferroptosis by Tumor Suppressor p53 and its Pathway

Liu

Zhang

Wang

et al. 2020

IJMS

134

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“…Mitochondria are indispensable for numerous cellular processes, such as respiratory energy metabolism, cell proliferation, apoptosis, senescence, and immune response (13). Mitochondrial DNA (mtDNA) is a circular DNA molecule of 16,569 bp containing 2 rRNA, 22 tRNA, and 13 genes encoding protein subunits for the mitochondrial complexes of the oxidative phosphorylation system (OXPHOS).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial DNA Mutation Analysis in Breast Cancer: Shifting From Germline Heteroplasmy Toward Homoplasmy in Tumors

et al. 2020

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Studies have suggested a potential role of somatic mitochondrial mutations in cancer development. To analyze the landscape of somatic mitochondrial mutation in breast cancer and to determine whether mitochondrial DNA (mtDNA) mutational burden is correlated with overall survival (OS), we sequenced whole mtDNA from 92 matchedpaired primary breast tumors and peripheral blood. A total of 324 germline variants and 173 somatic mutations were found in the tumors. The most common germline allele was 663G (12S), showing lower heteroplasmy levels in peripheral blood lymphocytes than in their matched tumors, even reaching homoplasmic status in several cases. The heteroplasmy load was higher in tumors than in their paired normal tissues. Somatic mtDNA mutations were found in 73.9% of breast tumors; 59% of these mutations were located in the coding region (66.7% non-synonymous and 33.3% synonymous). Although the CO1 gene presented the highest number of mutations, tRNA genes (T, C, and W), rRNA 12S, and CO1 and ATP6 exhibited the highest mutation rates. No specific mtDNA mutational profile was associated with molecular subtypes of breast cancer, and we found no correlation between mtDNA mutational burden and OS. Future investigations will provide insight into the molecular mechanisms through which mtDNA mutations and heteroplasmy shifting contribute to breast cancer development.

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“…DHA activated apoptosis via caspase-3, followed by PARP cleavage (Figure 3A), and decreased ψ m (Figure 5B), which in turn, increased the translocation of Cyt C from the mitochondria to the cytoplasm ( Figure 5C) (45). Additionally, DHA interacted with iron and activated oxygen consumption (Figures 2B,C), resulting in increased production of ROS (Figures 2A, 5A), and this was assumed to be the after-effects of permeabilization of the outer mitochondrial membrane (46), since outer mitochondrial membrane permeabilization resulted in a loss of ψ m and an increase in ROS levels (47). For MM treatment, the drug resistance and its related relapse are the major clinical obstacles, we further explored that DHA is effective in treating drugresistant MM (Figures 4A,B).…”

Section: Discussionmentioning

confidence: 97%

Dihydroartemisinin Induces Growth Arrest and Overcomes Dexamethasone Resistance in Multiple Myeloma

Chen

Zhu

et al. 2020

Front. Oncol.

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The discovery of artemisinin (ART) for malaria treatment won the 2015 Nobel Prize in Medicine, which inspired the rediscovery and development of ART for the treatment of other diseases including cancer. In this study, we investigated the potential therapeutic effect of ART and dihydroartemisinin (DHA) on multiple myeloma (MM) cells including primary MM cells and in 5TMM3VT mouse model. Both in vitro and in vivo experiments showed that DHA might be a more promising anti-MM agent with significantly improved efficacy compared to ART. Mechanistic analyses suggested that DHA activated the mitochondrial apoptotic pathway by interacting with ferrous (Fe 2+) ions and oxygen to produce reactive oxygen species (ROS). Intriguingly, DHA could reverse the upregulated expression of B-cell lymphoma 2 (Bcl-2) protein, a typical mitochondrial apoptotic marker, induced by dexamethasone (Dexa) in MM. We further demonstrated that DHA treatment could overcome Dexa resistance and enhance Dexa efficacy in MM. Additionally, DHA combined with Dexa resulted in increased ROS production and cytochrome C translocation from the mitochondria to the cytoplasm, resulting in alterations to the mitochondrial membrane potential and caspase-mediated apoptosis. In summary, our study demonstrated that DHA was superior to ART in MM treatment and overcame Dexa resistance both in vitro and in vivo, providing a promising therapeutic strategy for MM therapy.

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Mitochondria: promising organelle targets for cancer diagnosis and treatment

Cited by 66 publications

References 89 publications

The Regulation of Ferroptosis by Tumor Suppressor p53 and its Pathway

The Regulation of Ferroptosis by Tumor Suppressor p53 and its Pathway

Mitochondrial DNA Mutation Analysis in Breast Cancer: Shifting From Germline Heteroplasmy Toward Homoplasmy in Tumors

Dihydroartemisinin Induces Growth Arrest and Overcomes Dexamethasone Resistance in Multiple Myeloma

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