The interplay between DNA repair and autophagy in cancer therapy

Zhang, Dan; Tang, Bo; Xie, Xing; Xiao, Yonglong; Yang, Shiming; Zhang, Jianwei

doi:10.1080/15384047.2015.1046022

Cited by 99 publications

(86 citation statements)

References 111 publications

(119 reference statements)

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“…It was demonstrated that the induction of autophagy is associated with DNA damage (55)(56)(57). Autophagy has been shown to regulate some of the DNA repair proteins after DNA damage (55)(56)(57). One the other hand, some evidence has demonstrated that some DNA repair molecular have a crucial role in the initiation of autophagy (58,59).…”

Section: Discussionmentioning

confidence: 99%

“…The role of autophagy in carcinogenesis is context-dependent. It was demonstrated that the induction of autophagy is associated with DNA damage (55)(56)(57). Autophagy has been shown to regulate some of the DNA repair proteins after DNA damage (55)(56)(57).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, autophagy could play a dual role in cancer by facilitating either cell death or cell survival. Autophagy is considered to be a tumor-suppressing mechanism in early-stage carcinogenesis and may mediate the therapeutic effect of anticancer agents (54,55). However, autophagy may also act as a pro-survival mechanism to protect cancer cells from various forms of cellular stress (64).…”

Section: Discussionmentioning

confidence: 99%

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2-Methoxyestradiol Reverses the Pro-Carcinogenic Effect of L-Lactate in Osteosarcoma 143B Cells

Górska‐Ponikowska

Kuban–Jankowska

Daca

et al. 2017

CGP

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Abstract. Background Cancer cells are traditionally characterized by increased glucose uptake, high rates of aerobic glycolysis, increased lactic acid production, impaired mitochondrial function and decreased extracellular pH. These characteristics are known as the 'Warburg effect' (1-3). The 'Warburg effect' is also observed in cancer-associated fibroblasts and mesenchymal stem cells (1-11), which secrete lactate and ketones into the microenvironment of the tumor. Lactic acid exists as L-and D-optical isomers. In mammals including humans, lactate is present almost entirely as L-lactate (12, 13). Interestingly, a variety of human cancer cell lines and human tumors, including breast, prostate, head, neck, and osteosarcoma cancers, import these metabolites and deliver them to the mitochondrial TCA cycle, thereby promoting ATP generation and cell proliferation (1-14). According to this 'reverse Warburg effect', tumor cells can induce metabolic reprogramming by shuttling lactate as an energy source to neighboring cancer cells, to the adjacent stroma and to vascular endothelial cells (1,14).Tumors contain both aerobic and hypoxic regions that form a metabolic symbiosis that is crucial for tumor cell survival (15, 16). The cancer cells located in the hypoxic regions export lactate, which acidifies the tumor environment; the cells located in the aerobic regions, however, import lactate and utilize it for oxidative phosphorylation (4). Bonuccelli and colleagues (2) suggested that L-lactate metabolism in cancer cells may explain why diabetic patients have an increased risk of cancer development and a tendency towards autophagy/mitophagy in their adipose tissue. An increased tumor L-lactate level strictly correlates with increased metastasis, tumor recurrence and poor outcome (6-9).L-lactate metabolism and the reverse Warburg effect has been clearly established in osteosarcoma cells. It has been demonstrated that the secretion of lactate and ketones by the mesenchymal stem cells drives mitochondrial biogenesis and increases the mitochondrial activity in osteosarcoma cells (1, 483 This article is freely accessible online.Correspondence to: Magdalena Gorska-Ponikowska (MGP),

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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2-Methoxyestradiol Reverses the Pro-Carcinogenic Effect of L-Lactate in Osteosarcoma 143B Cells

Górska‐Ponikowska

Kuban–Jankowska

Daca

et al. 2017

CGP

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“…Thus, ROS mediated Cuc B-induced DNA damage, apoptosis, and autophagy in BEL-7402 cells. DNA damage-induced apoptosis has been well recognized while its role in autophagy remains unclear [45]. Here, we found that Cuc B-induced autophagy was inhibited by KU55933 and caffeine while 3-MA and CQ showed no effect on DNA damage.…”

Section: Discussionmentioning

confidence: 70%

PTEN Activation by DNA Damage Induces Protective Autophagy in Response to Cucurbitacin B in Hepatocellular Carcinoma Cells

Niu

Sun

et al. 2016

Oxidative Medicine and Cellular Longevity

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Cucurbitacin B (Cuc B), a natural product, induced both protective autophagy and DNA damage mediated by ROS while the detailed mechanisms remain unclear. This study explored the mechanism of Cuc B-induced DNA damage and autophagy. Cuc B decreased cell viability in concentration- and time-dependent manners. Cuc B caused long comet tails and increased expression of γ-H2AX, phosphorylation of ATM/ATR, and Chk1/Chk2. Cuc B induced autophagy as evidenced by monodansylcadaverine (MDC) staining, increased expression of LC3II, phosphorylated ULK1, and decreased expression of phosphorylated AKT, mTOR. Cuc B induced apoptosis mediated by Bcl-2 family proteins and caspase activation. Furthermore, Cuc B induced ROS formation, which was inhibited by N-acetyl-L-cysteine (NAC). NAC pretreatment dramatically reversed Cuc B-induced DNA damage, autophagy, and apoptosis. Cuc B-induced apoptosis was reversed by NAC but enhanced by 3-methyladenine (3-MA), chloroquine (CQ), and silencing phosphatase and tensin homolog (PTEN). 3-MA and CQ showed no effect on Cuc B-induced DNA damage. In addition, Cuc B increased PTEN phosphorylation and silence PTEN restored Cuc B-induced autophagic protein expressions without affecting DNA damage. In summary, Cuc B induced DNA damage, apoptosis, and protective autophagy mediated by ROS. PTEN activation in response to DNA damage bridged DNA damage and prosurvival autophagy.

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“…However, when severe damage is beyond repair, cell death occurs. Thus, autophagy can play a dual role in determining cell fate by two process, not only can it play a protective role, but autophagy can also lead to cell death [44]. Autophagy can induce an adaptive response to protect against chemical mutagens and ionizing radiation [45][46][47][48].…”

Section: Discussionmentioning

confidence: 99%

The Protective Effect of Autophagy on DNA Damage in Mouse Spermatocyte-Derived Cells Exposed to 1800 MHz Radiofrequency Electromagnetic Fields

et al. 2018

Cell Physiol Biochem

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Background/Aims: The effects of exposure to radiofrequency electromagnetic fields (RF-EMFs) on the male reproductive system have raised public concern and studies have shown that exposure to RF-EMFs can induce DNA damage and autophagy. However, there are no related reports on the role of autophagy in DNA damage in spermatocytes, especially after exposure to RF-EMFs. The aim of the present study was to determine the mechanism and role of autophagy induced by RF-EMFs in spermatozoa cells. Methods: Mouse spermatocyte-derived cells (GC-2) were exposed to RF-EMFs 4 W/kg for 24 h. The level of reactive oxygen species (ROS) was determined by ROS assay kit. Comet assay was utilized to detect DNA damage. Autophagy was detected by three indicators: LC3II/LC3I, autophagic vacuoles, and GFP-LC3 dots, which were measured by western blot, transmission electron microscopy, and transfection with GFP-LC3, respectively. The expression of the molecular signaling pathway AMP-activated protein kinase (AMPK)/mTOR was determined by western blot. Results: The results showed that RF-EMFs induced autophagy and DNA damage in GC-2 cells via ROS generation, and the autophagy signaling pathway AMPK/mTOR was activated by ROS generation. Furthermore, following inhibition of autophagy by knockdown of AMPKα, increased DNA damage was observed in GC-2 cells following RF-EMFs exposure, and overexpression of AMPKα promoted autophagy and attenuated DNA damage. Conclusions: These findings demonstrated that the autophagy which was induced by RF-EMFs via the AMPK/mTOR signaling pathway could prevent DNA damage in spermatozoa cells.

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The interplay between DNA repair and autophagy in cancer therapy

Cited by 99 publications

References 111 publications

2-Methoxyestradiol Reverses the Pro-Carcinogenic Effect of L-Lactate in Osteosarcoma 143B Cells

2-Methoxyestradiol Reverses the Pro-Carcinogenic Effect of L-Lactate in Osteosarcoma 143B Cells

PTEN Activation by DNA Damage Induces Protective Autophagy in Response to Cucurbitacin B in Hepatocellular Carcinoma Cells

The Protective Effect of Autophagy on DNA Damage in Mouse Spermatocyte-Derived Cells Exposed to 1800 MHz Radiofrequency Electromagnetic Fields

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