Unravelling the relationship between macroautophagy and mitochondrial ROS in cancer therapy

Zhao, Yuqian; Qu, Tiange; Wang, Peiqi; Li, Xinyi; Qiang, Jiayu; Xia, Zhaokun; Duan, Hangwu; Huang, Jian; Zhu, Lingjuan

doi:10.1007/s10495-016-1236-3

Cited by 34 publications

(26 citation statements)

References 146 publications

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“…The activation of autophagy (often mediated by mitochondrial ROS [48]) is necessary to degrade misfolded or damaged cell components, including mitochondria, thus promoting cancer cell survival. However, under extreme conditions, it can act as programmed cell death mechanism type II [49].…”

Section: Discussionmentioning

confidence: 99%

Molecular features of the cytotoxicity of an NHE inhibitor: Evidence of mitochondrial alterations, ROS overproduction and DNA damage

et al. 2016

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BackgroundNH exchangers (NHEs) play a crucial role in regulating intra/extracellular pH, which is altered in cancer cells, and are therefore suitable targets to alter cancer cell metabolism in order to inhibit cell survival and proliferation. Among NHE inhibitors, amiloride family members are commonly used in clinical practice as diuretics; we focused on the amiloride HMA, reporting a net cytotoxic effect on a panel of human cancer cell lines; now we aim to provide new insights into the molecular events leading to cell death by HMA.MethodsColon cancer cell lines were treated with HMA and analysed with: morphological and cellular assays for cell viability and death, and autophagy; biochemical approaches to evaluate mitochondrial function and ROS production; in situ detection of DNA damage; molecular tools to silence crucial autophagy/necroptosis factors.ResultsHMA affects cellular morphology, alters mitochondrial structure and function, causes an increase in ROS, which is detrimental to DNA integrity, stimulates poly(ADP-ribose) synthesis, activates RIPK3-dependent death and triggers autophagy, which is unable to rescue cell survival. These features are hot points of an intricate network of processes, including necroptosis and autophagy, regulating the homeostasis between survival and death.ConclusionOur results allow the identification of multiple events leading to cell death in cancer cells treated with HMA. The here-defined intricate network activated by HMA could be instrumental to selectively target the key players of each pathway in the attempt to improve the global response to HMA. Our data could be the starting point for developing a newly designed targeted therapy.

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Section: Discussionmentioning

confidence: 99%

Molecular features of the cytotoxicity of an NHE inhibitor: Evidence of mitochondrial alterations, ROS overproduction and DNA damage

et al. 2016

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“…During the initiation of apoptosis, an abnormal increase in ROS occurs, which is an important stimulus for mitochondrial apoptosis (35). It has been demonstrated that a number of drugs induce apoptosis of cancer cells by increasing ROS levels (36,37).…”

Section: Discussionmentioning

confidence: 99%

Luteolin induces mitochondrial apoptosis in HT29 cells by inhibiting the Nrf2/ARE signaling pathway

et al. 2020

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The aim of the current study was to investigate luteolin-induced apoptosis and the molecular mechanisms underlying it in HT29 cells. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to assess the cytotoxicity of luteolin on HT29 cells, and a dichloro-dihydro-fluorescein diacetate assay was used to measure cellular levels of reactive oxygen species (ROS). The effects of luteolin on the mitochondrial membrane potential were also evaluated. Bax and Bcl-2 mRNA expression were determined using reverse transcription-quantitative PCR. Additionally, western blot analysis was performed to assess changes in cytochrome c and caspase-3 protein expression. Localization of nuclear factor erythroid 2-related factor 2 (Nrf2) in the nucleus was also assessed using immunofluorescence. Luteolin exhibited cytotoxicity on HT29 cells in a time-and concentration-dependent manner. Additionally, ROS production was indicated to be increased and ROS scavenging was decreased, which resulted in a significant increase in the levels of ROS in the cells. The mitochondrial membrane potential was indicated to decrease following luteolin treatment. At the molecular level, luteolin significantly increased the mRNA expression of Bax and the protein expression of cytochrome c, caspase-3, p47 phox and p22 phox . The results revealed that luteolin decreased Bcl-2 protein expression and inhibited the nuclear localization of Nrf2. In conclusion, the current study indicated that luteolin inhibited HT29 cell proliferation and induced apoptosis via the mitochondrial pathway.

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“…ROS have multifaceted effects, and the function of ROS is determined by the redox state (Zhao et al, 2016). Oxidative stress is induced when ROS are produced in excess of the capacity of the antioxidant system to efficiently counteract their actions, resulting in cytotoxic effects and enhancing periodontal destruction (Nibali and Donos, 2013).…”

Section: Ros In Periodontitismentioning

confidence: 99%

“…Studies suggest that ROS influence autophagy and that autophagy reciprocally regulates ROS (He Y. et al, 2017; Wang et al, 2017). The most typical example of their interaction has been elucidated in cancer development (Zhao et al, 2016). Autophagy consists of five sequential steps: induction, elongation, maturation, transport to lysosomes, and degradation (Levine and Kroemer, 2008).…”

Section: Introductionmentioning

confidence: 99%

The Role of Reactive Oxygen Species and Autophagy in Periodontitis and Their Potential Linkage

et al. 2017

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Periodontitis is a chronic inflammatory disease that causes damage to periodontal tissues, which include the gingiva, periodontal ligament, and alveolar bone. The major cause of periodontal tissue destruction is an inappropriate host response to microorganisms and their products. Specifically, a homeostatic imbalance between reactive oxygen species (ROS) and antioxidant defense systems has been implicated in the pathogenesis of periodontitis. Elevated levels of ROS acting as intracellular signal transducers result in autophagy, which plays a dual role in periodontitis by promoting cell death or blocking apoptosis in infected cells. Autophagy can also regulate ROS generation and scavenging. Investigations are ongoing to elucidate the crosstalk mechanisms between ROS and autophagy. Here, we review the physiological and pathological roles of ROS and autophagy in periodontal tissues. The redox-sensitive pathways related to autophagy, such as mTORC1, Beclin 1, and the Atg12-Atg5 complex, are explored in depth to provide a comprehensive overview of the crosstalk between ROS and autophagy. Based on the current evidence, we suggest that a potential linkage between ROS and autophagy is involved in the pathogenesis of periodontitis.

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Unravelling the relationship between macroautophagy and mitochondrial ROS in cancer therapy

Cited by 34 publications

References 146 publications

Molecular features of the cytotoxicity of an NHE inhibitor: Evidence of mitochondrial alterations, ROS overproduction and DNA damage

Molecular features of the cytotoxicity of an NHE inhibitor: Evidence of mitochondrial alterations, ROS overproduction and DNA damage

Luteolin induces mitochondrial apoptosis in HT29 cells by inhibiting the Nrf2/ARE signaling pathway

The Role of Reactive Oxygen Species and Autophagy in Periodontitis and Their Potential Linkage

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