Late-responding normal tissue cells benefit from high-precision radiotherapy with prolonged fraction delivery times via enhanced autophagy

Yao, Qingzhou; Zheng, Rong; Xie, Guozhu; Liao, Guixiang; Du, Shasha; Ren, Chen; Li, Rong; Lin, Xia; Hu, Daokun; Yuan, Yawei

doi:10.1038/srep09119

Cited by 11 publications

(7 citation statements)

References 26 publications

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“…Alexander et al found that ATM plays an important role in autophagy induced by IR and ROS. 49 In our previous work, we found that ATM was activated by IR and further triggered autophagy in HeLa and H1299 cells. ATM was activated by IR and ROS treatments and subsequently triggered the LKB1-AMPK-TSC2 pathway to induce autophagy by suppressing mTORC1.…”

Section: The Functions Of Atm In Nonselective Autophagy In Cancermentioning

confidence: 90%

“…39 Late-responding normal tissues showed more benefits from prolonged fraction delivery time (FDTs) than acute-responding tissues because of induced autophagy via the ATM-AMPK pathway. 49 In our previous work, we found that ATM was activated by IR and further triggered autophagy in HeLa and H1299 cells. 34,50 We also found that MAPK14 was one of the ATM substrates.…”

Section: The Functions Of Atm In Nonselective Autophagy In Cancermentioning

confidence: 90%

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Multifaceted roles of ATM in autophagy: From nonselective autophagy to selective autophagy

Liang

Liu

et al. 2019

Cell Biochemistry & Function

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The ataxia-telangiectasia mutated (ATM) protein kinase is best known for its critical nuclear roles in the DNA damage response (DDR), cell cycle checkpoints, and the maintenance of gene stability. In this review, we highlight the multifaceted cytoplasmic functions of ATM in autophagy. We focused on the functions of ATM in nonselective autophagy in cancer. An Oncomine database analysis showed a tight association between ATM and autophagy in various cancers. In particular, its mechanisms in nonselective autophagy, those induced by ionizing radiation (IR), are illustrated in detail and involve the MAPK14 pathway, mTOR pathway, and Beclin1/PI3KIII complexes. Recently, an increasing number of studies revealed that autophagy could also be highly selective. We additionally emphasized the novel roles of ATM in selective autophagy, including mitophagy, pexophagy, and lipophagy. The regulation of these processes mainly involves ATM-PEX5, ATM-AMPK-TSC2-mTORC1-ULK1, PPM1D-ATM-MTOR, PINK I/Parkin, and NAD+/ SIRT1. We aimed to provide new perspectives on the importance of ATM in the diverse field of autophagy. The intricate regulation of ATM in autophagy still requires further investigation, which would enhance our understanding of its role in cell dynamics and homeostasis.Significance of the study Our review highlighted the multifaceted cytoplasmic functions of ATM on autophagy. First, we focused on the functions of ATM in nonselective autophagy within cancer especially those induced by IR, involving the MAPK14 pathway, mTOR pathway, and Beclin1/PI3KIII complexes. These provided a theoretical understanding of tumour radiosensitivity and chemosensitivity. In addition, we emphasized the novel roles of ATM in selective autophagy, including mitophagy, pexophagy, and lipophagy. This review provides new perspectives on the importance of ATM in the diverse field of autophagy, which would provide more information on its role in whole cell dynamics and homeostasis.

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Section: The Functions Of Atm In Nonselective Autophagy In Cancermentioning

confidence: 90%

Section: The Functions Of Atm In Nonselective Autophagy In Cancermentioning

confidence: 90%

Multifaceted roles of ATM in autophagy: From nonselective autophagy to selective autophagy

Liang

Liu

et al. 2019

Cell Biochemistry & Function

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“…The protein kinase ataxia-telangiectasia mutated (ATM), best known for its role as a prime mediator of the DNA damage response 28 29 30 , is also active in other cell signaling pathways involved in maintaining cellular homeostasis 31 32 33 34 35 36 37 38 39 . ATM regulates autophagy by activating tuberous sclerosis complex2 (TSC2) or by phosphorylating the transcription regulator hypoxia-inducible factor 1α (HIF1α) to modulate redox homeostasis 40 41 42 .…”

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confidence: 99%

ATM mediates spermidine-induced mitophagy via PINK1 and Parkin regulation in human fibroblasts

Qiu

et al. 2016

Sci Rep

101

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The ATM (ataxia telangiectasia mutated) protein has recently been proposed to play critical roles in the response to mitochondrial dysfunction by initiating mitophagy. Here, we have used ATM-proficient GM00637 cells and ATM-deficient GM05849 cells to investigate the mitophagic effect of spermidine and to elucidate the role of ATM in spermdine-induced mitophagy. Our results indicate that spermidine induces mitophagy by eliciting mitochondrial depolarization, which triggers the formation of mitophagosomes and mitolysosomes, thereby promoting the accumulation of PINK1 and translocation of Parkin to damaged mitochondria, finally leading to the decreased mitochondrial mass in GM00637 cells. However, in GM05849 cells or GM00637 cells pretreated with the ATM kinase inhibitor KU55933, the expression of full-length PINK1 and the translocation of Parkin are blocked, and the colocalization of Parkin with either LC3 or PINK1 is disrupted. These results suggest that ATM drives the initiation of the mitophagic cascade. Our study demonstrates that spermidine induces mitophagy through ATM-dependent activation of the PINK1/Parkin pathway. These findings underscore the importance of a mitophagy regulatory network of ATM and PINK1/Parkin and elucidate a novel mechanism by which ATM influences spermidine-induced mitophagy.

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“…Thus, dose and volume reduction for the normal liver is required in order to improve the effects of radiotherapy for massive HCC. In addition, HCC is an early response tissue, whereas normal liver is a late response tissue (29). According to the principle of radiobiology, in order to reduce the radiation damage to the normal liver, the split dose should generally be ≤2 Gy (30).…”

Section: Discussionmentioning

confidence: 99%

Clinical research on alternating hyperfraction radiotherapy for massive hepatocellular carcinoma

et al. 2015

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Abstract. The delivery of high tumoricidal doses of radiation with low rates of toxicity is of particular significance for massive hepatocellular carcinoma (HCC) radiotherapy. In order to observe the efficacy and adverse reactions of alternating hyperfraction radiotherapy treatment of massive HCC, seventy-two cases of massive HCC were randomly divided into two groups, group A and group B. The liver lesions of group A were divided into sublesions and treated with alternating hyperfraction radiotherapy [intensity modulated radiotherapy (IMRT)]. The interval between radiotherapy to the sublesions was a minimum of six hours. The average radiotherapy dose to the sublesions was 2 Gy/fraction, once a day, five times per week, treating the gross tumor volume with a total dose of 40-50 Gy, and the clinical target volume with a total dose of 30-40 Gy. By contrast, the lesions of group B were not divided into sublesions for the IMRT treatment, but were treated with an otherwise identical protocol, by 2 Gy/fraction, once a day, five times per week, and with the same total dose. Patients were followed up with regular blood tests, liver function tests, measurements of serum α-fetoprotein levels and contrast-enhanced magnetic resonance imaging (MRI) of the liver. Treatment responses were assessed every 3 months by MRI. The results revealed that the overall response rates of the two groups were 82.9 and 81.3%, respectively (P=0.864). The alternating hyperfraction radiotherapy protocol resulted in enhanced survival (P=0.002). The median survival time of the two groups was 9.7 and 6.5 months, respectively. The overall 6-month, 1-year, 2-year and 3-year survival rates of the two groups were 62.9 and 59.4% (P=0.770), 48.6 and 21.9% (P=0.040), 17.1 and 0.0% (P=0.025) and 2.9 and 0.0% (P=1.000), respectively. The Ⅰ-Ⅱ degree of abnormal liver function and radiation-induced liver disease of group B was higher than that of group A (P=0.021 and 0.046, respectively). In addition, the incidence rate of radiation-induced liver injury of group A was lower than that of group B. Therefore, treatment of massive HCC with alternating hyperfraction radiotherapy improved the quality of life and prolonged the overall survival time, compared with conventional IMRT, suggesting that it was an effective radiation pattern.

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Late-responding normal tissue cells benefit from high-precision radiotherapy with prolonged fraction delivery times via enhanced autophagy

Cited by 11 publications

References 26 publications

Multifaceted roles of ATM in autophagy: From nonselective autophagy to selective autophagy

Multifaceted roles of ATM in autophagy: From nonselective autophagy to selective autophagy

ATM mediates spermidine-induced mitophagy via PINK1 and Parkin regulation in human fibroblasts

Clinical research on alternating hyperfraction radiotherapy for massive hepatocellular carcinoma

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