The Role and Mechanism of ATM-Mediated Autophagy in the Transition From Hyper-Radiosensitivity to Induced Radioresistance in Lung Cancer Under Low-Dose Radiation

Wang, Qiong; Chen, Yangyang; Chang, Haiyan; Hu, Ting; Wang, Jue; Xie, Yuxiu; Cheng, Jing

doi:10.3389/fcell.2021.650819

Cited by 12 publications

(7 citation statements)

References 27 publications

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“…A similar conclusion can be reached with the cell cycle since all the cell lines have been irradiated in similar distributions of cell cycle phases. Our results were found to be in agreement with literature data [28][29][30] (Figure 2). 2 were fitted to S(D) = exp(−αres (1 + g exp(−D/Dc))D−βD 2 ) (Formula (2)).…”

Section: Hrs Status Of the 6 Tumor Cell Lines Used In This Studysupporting

confidence: 93%

Influence of the Hypersensitivity to Low Dose Phenomenon on the Tumor Response to Hypofractionated Stereotactic Body Radiation Therapy

Le Reun,

Granzotto,

Pêtre

et al. 2023

Cancers

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Stereotactic body radiation therapy (SBRT) has made the hypofractionation of high doses delivered in a few sessions more acceptable. While the benefits of hypofractionated SBRT have been attributed to additional vascular, immune effects, or specific cell deaths, a radiobiological and mechanistic model is still needed. By considering each session of SBRT, the dose is divided into hundreds of minibeams delivering some fractions of Gy. In such a dose range, the hypersensitivity to low dose (HRS) phenomenon can occur. HRS produces a biological effect equivalent to that produced by a dose 5-to-10 times higher. To examine whether HRS could contribute to enhancing radiation effects under SBRT conditions, we exposed tumor cells of different HRS statuses to SBRT. Four human HRS-positive and two HRS-negative tumor cell lines were exposed to different dose delivery modes: a single dose of 0.2 Gy, 2 Gy, 10 × 0.2 Gy, and a single dose of 2 Gy using a non-coplanar isocentric minibeams irradiation mode were delivered. Anti-γH2AX immunofluorescence, assessing DNA double-strand breaks (DSB), was applied. In the HRS-positive cells, the DSB produced by 10 × 0.2 Gy and 2 Gy, delivered by tens of minibeams, appeared to be more severe, and they provided more highly damaged cells than in the HRS-negative cells, suggesting that more severe DSB are induced in the “SBRT modes” conditions when HRS occurs in tumor. Each SBRT session can be viewed as hyperfractionated dose delivery by means of hundreds of low dose minibeams. Under current SBRT conditions (i.e., low dose per minibeam and not using ultra-high dose-rate), the response of HRS-positive tumors to SBRT may be enhanced significantly. Interestingly, similar conclusions were reached with HRS-positive and HRS-negative untransformed fibroblast cell lines, suggesting that the HRS phenomenon may also impact the risk of post-RT tissue overreactions.

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Section: Hrs Status Of the 6 Tumor Cell Lines Used In This Studysupporting

confidence: 93%

Influence of the Hypersensitivity to Low Dose Phenomenon on the Tumor Response to Hypofractionated Stereotactic Body Radiation Therapy

Le Reun,

Granzotto,

Pêtre

et al. 2023

Cancers

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“…AMBRA1 as an emerging haploinsufficient tumor suppressor plays a pivotal role in tumorigenesis and progression ( 26 , 45 ). Furthermore, AMBRA1-mediated autophagy plays controversial roles in chemoradiotherapy ( 78 , 79 , 81 – 84 ), and the different roles of AMBRA1-associated autophagy in cancer treatment seem to depend on tumor type, stage, and genetic context ( 76 ).…”

Section: Discussionmentioning

confidence: 99%

“…Radiation therapy is another classical cancer treatment scheme, and AMBRA1 also regulates tumor sensitivity to radiotherapy. AMBRA1-associated autophagy promotes the transition from hyper-radiosensitivity to induced radio-resistance in A549 and H460 human lung adenocarcinoma cell lines ( 84 ). Calcitriol, an active metabolite of vitamin D, enhances the sensitivity to irradiation in SiHa and CaSki cervical cancer cells by promoting AMBRA1 degradation ( 85 ).…”

Section: Ambra1—a Potential Target For Anticancer Therapymentioning

confidence: 99%

AMBRA1 and its role as a target for anticancer therapy

Yuan

et al. 2022

Front. Oncol.

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The activating molecule in Beclin1-regulated autophagy protein 1 (AMBRA1) is an intrinsically disordered protein that regulates the survival and death of cancer cells by modulating autophagy. Although the roles of autophagy in cancer are controversial and context-dependent, inhibition of autophagy under some circumstances can be a useful strategy for cancer therapy. As AMBRA1 is a pivotal autophagy-associated protein, targeting AMBRA1 similarly may be an underlying strategy for cancer therapy. Emerging evidence indicates that AMBRA1 can also inhibit cancer formation, maintenance, and progression by regulating c-MYC and cyclins, which are frequently deregulated in human cancer cells. Therefore, AMBRA1 is at the crossroad of autophagy, tumorigenesis, proliferation, and cell cycle. In this review, we focus on discussing the mechanisms of AMBRA1 in autophagy, mitophagy, and apoptosis, and particularly the roles of AMBRA1 in tumorigenesis and targeted therapy.

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“…However, recent evidence has strongly linked ATM to the induction and function of autophagy in response to genotoxic stress (reviewed in depth in [ 62 , 63 ]). For example, ATM regulates radiation-induced autophagy through the mTOR pathway [ 64 , 65 ], MAPK14 pathway [ 66 ], JNK pathway [ 67 ], and PI3KIII pathway [ 68 ], and complete lack of ATM function results in the failure of autophagy induction in tumor cells [ 68 , 69 , 70 ] or switches the cell stress response to senescence [ 71 ]. Conversely, Goehe et al showed that ATM knockdown attenuates both autophagy and senescence in response to chemotherapy [ 69 ], suggesting a more complicated role of ATM in regulating autophagy.…”

Section: Discussionmentioning

confidence: 99%

Effect of Autophagy Inhibitors on Radiosensitivity in DNA Repair-Proficient and -Deficient Glioma Cells

et al. 2022

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Background and Objectives: The development of radioresistance is a fundamental barrier to successful glioblastoma therapy. Autophagy is thought to play a role in facilitating the DNA repair of DNA damage foci in radiation-exposed tumor cells, thus, potentially contributing to their restoration of proliferative capacity and development of resistance in vitro. However, the effect of autophagy inhibitors on DNA damage repair is not fully clear and requires further investigation. Materials and Methods: In this work, we utilized M059K (DNA-PKcs proficient) and M059J (DNA-PKcs deficient) glioma cell lines to investigate the role of autophagy inhibitors in the DNA repair of radiation-induced DNA damage. Cell viability following radiation was determined by trypan blue exclusion in both cell lines. Cell death and autophagy assays were performed to evaluate radiation-induced cell stress responses. DNA damage was measured as based on the intensity of phosphorylated γ-H2AX, a DNA double-stranded breaks (DSBs) marker, in the presence or absence of autophagy inhibitors. Results: The cell viability assay showed that M059J cells were more sensitive to the same dose of radiation (4 Gy) than M059K cells. This observation was accompanied by an elevation in γ-H2AX formation in M059J but not in M059K cells. In addition, the DAPI/TUNEL and Senescence-associated β-galactosidase (SA-β-gal) staining assays did not reveal significant differences in apoptosis and/or senescence induction in response to radiation, respectively, in either cell line. However, acridine orange staining demonstrated clear promotion of acidic vesicular organelles (AVOs) in both cell lines in response to 4 Gy radiation. Moreover, DNA damage marker levels were found to be elevated 72 h post-radiation when autophagy was inhibited by the lysosomotropic agent bafilomycin A1 (BafA1) or the PI3K inhibitor 3-methyl adenine (3-MA) in M059K cells. Conclusions: The extent of the DNA damage response remained high in the DNA-PKcs deficient cells following exposure to radiation, indicating their inability to repair the newly formed DNA-DSBs. On the other hand, radioresistant M059K cells showed more DNA damage response only when autophagy inhibitors were used with radiation, suggesting that the combination of autophagy inhibitors with radiation may interfere with DNA repair efficiency.

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The Role and Mechanism of ATM-Mediated Autophagy in the Transition From Hyper-Radiosensitivity to Induced Radioresistance in Lung Cancer Under Low-Dose Radiation

Cited by 12 publications

References 27 publications

Influence of the Hypersensitivity to Low Dose Phenomenon on the Tumor Response to Hypofractionated Stereotactic Body Radiation Therapy

Influence of the Hypersensitivity to Low Dose Phenomenon on the Tumor Response to Hypofractionated Stereotactic Body Radiation Therapy

AMBRA1 and its role as a target for anticancer therapy

Effect of Autophagy Inhibitors on Radiosensitivity in DNA Repair-Proficient and -Deficient Glioma Cells

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