The Tumor Suppressor, p53, Contributes to Radiosensitivity of Lung Cancer Cells by Regulating Autophagy and Apoptosis

Cheng, Guanghui; Kong, Dejuan; Hou, Xue; Liu, Bing; He, Mingming; Liang, Nan; Ma, Shumei; Liu, Xiaodong

doi:10.1089/cbr.2012.1297

Cited by 41 publications

(38 citation statements)

References 22 publications

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“…Recent literature has shown that TP53 is involved in regulating autophagy via the MTOR-AMPK pathway in lung cancer cells. 36 Our previous work established that TP53 is required for sensitization to radiation in breast tumor cells 18,19 and this appears to be the case for NSCLC cells as well, since H358 cells with mutant TP53 did not demonstrate any radio-sensitization by EB 1089. Furthermore, sensitization to radiation by EB 1089 could not be shown in the tp53-null, VDR-expressing H1299 cell line unless TP53 expression was induced under the influence of doxycycline.…”

Section: Discussionmentioning

confidence: 84%

A novel cytostatic form of autophagy in sensitization of non-small cell lung cancer cells to radiation by vitamin D and the vitamin D analog, EB 1089

Sharma¹

2014

Autophagy

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The standard of care for unresectable lung cancer is chemoradiation. However, therapeutic options are limited and patients are rarely cured. We have previously shown that vitamin D and vitamin D analogs such as EB 1089 can enhance the response to radiation in breast cancer through the promotion of a cytotoxic form of autophagy. In A549 and H460 non-small cell lung cancer (NSCLC) cells, 1,25-D3 (the hormonally active form of vitamin D) and EB 1089 prolonged the growth arrest induced by radiation alone and suppressed proliferative recovery, which translated to a significant reduction in clonogenic survival. In H838 or H358 NSCLC cells, which lack VDR/vitamin D receptor or functional TP53, respectively, 1,25-D3 failed to modify the extent of radiation-induced growth arrest or suppress proliferative recovery post-irradiation. Sensitization to radiation in H1299 NSCLC cells was evident only when TP53 was induced in otherwise tp53-null H1299 NSCLC cells. Sensitization was not associated with increased DNA damage, decreased DNA repair or an increase in apoptosis, necrosis, or senescence. Instead sensitization appeared to be a consequence of the conversion of the cytoprotective autophagy induced by radiation alone to a novel cytostatic form of autophagy by the combination of 1,25-D3 or EB 1089 with radiation. While both pharmacological and genetic suppression of autophagy or inhibition of AMPK phosphorylation sensitized the NSCLC cells to radiation alone, inhibition of the cytostatic autophagy induced by the combination treatment reversed sensitization. Evidence for selectivity was provided by lack of radiosensitization in normal human bronchial cells and cardiomyocytes. Taken together, these studies have identified a unique cytostatic function of autophagy that appears to be mediated by VDR, TP53, and possibly AMPK in the promotion of an enhanced response to radiation by 1,25-D3 and EB 1089 in NSCLC.

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Section: Discussionmentioning

confidence: 84%

A novel cytostatic form of autophagy in sensitization of non-small cell lung cancer cells to radiation by vitamin D and the vitamin D analog, EB 1089

Sharma¹

2014

Autophagy

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“…For example, Cheng et al . demonstrated that p53 upregulation increased the sensitivity of lung adenocarcinoma cells to radiation, mediated by reduced autophagy . In contrast, Kim et al .…”

Section: Introductionmentioning

confidence: 86%

“…For example, Cheng et al demonstrated that p53 upregulation increased the sensitivity of lung adenocarcinoma cells to radiation, mediated by reduced autophagy. 16 In contrast, Kim et al reported that increased autophagy by mammalian target of rapamycin (mTOR) inhibitors sensitized lung cancer cells to radiation. 17 This may indicate that autophagy has dual effects, in which cell survival is promoted and cell death is induced in cancer cells in a context-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

Rapamycin‐induced autophagy sensitizes A549 cells to radiation associated with DNA damage repair inhibition

Liu

Wang

et al. 2016

Thoracic Cancer

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BackgroundAutophagy has been reported to increase in cancer cells after radiation. However, it remains unknown whether increased autophagy as a result of radiation affects DNA damage repair and sensitizes cancer cells. In this study, the radiosensitization effect of rapamycin, a mammalian target of rapamycin inhibitor that induces autophagy, on human lung adenocarcinoma A549 cells was investigated.MethodsA549 cells were treated with different concentrations of rapamycin. Cell viability was evaluated by methyl‐thiazolyl‐tetrazolium assay. Survival fraction values of A549 cells after radiotherapy were detected by colony formation assay. Autophagosome was observed by a transmission electron microscope. Furthermore, Western blot was employed to examine alterations in autophagy protein LC3 and p62, DNA damage protein γ–H2AX, and DNA damage repair proteins Rad51, Ku70, and Ku80. Rad51, Ku70, and Ku80 messenger ribonucleic acid (mRNA) expression levels were examined by real‐time polymerase chain reaction.ResultsRapamycin suppressed A549 cell proliferation in dose and time‐dependent manners. An inhibitory concentration (IC) 10 dose of rapamycin could induce autophagy in A549 cells. Rapamycin combined with radiation significantly decreased the colony forming ability of cells, compared with rapamycin or radiation alone. Rapamycin and radiation combined increased γ–H2AX expression levels and decreased Rad51 and Ku80 expression levels, compared with single regimens. However, rapamycin treatment did not induce any change in Rad51, Ku70, and Ku80 mRNA levels, regardless of radiation.ConclusionsThese findings indicate that increasing autophagy sensitizes lung cancer cells to radiation.

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“…In mammalian cells, Vps34, in complex with its regulatory subunits such as Beclin 1 and Atg14L, is an important regulator of autophagy (Simonsen and Tooze 2009;Funderburk et al 2010). Although DNA damage has been shown to lead to suppression of autophagy in a p53-dependent manner (Cheng et al 2013), the mechanism by which the transcriptional regulation of p53 leads to suppression of autophagy upon DNA damage response is not clear.…”

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confidence: 99%

FBXL20-mediated Vps34 ubiquitination as a p53 controlled checkpoint in regulating autophagy and receptor degradation

Xiao

Zhang

et al. 2015

Genes Dev.

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Vacuolar protein-sorting 34 (Vps34), the catalytic subunit in the class III PtdIns3 (phosphatidylinositol 3) kinase complexes, mediates the production of PtdIns3P, a key intracellular lipid involved in regulating autophagy and receptor degradation. However, the signal transduction pathways by which extracellular signals regulate Vps34 complexes and the downstream cellular mechanisms are not well understood. Here we show that DNA damageactivated mitotic arrest and CDK activation lead to the phosphorylation of Vps34, which provides a signal to promote its ubiquitination and proteasomal degradation mediated by FBXL20 (an F-box protein) and the associated Skp1 (S-phase kinase-associated protein-1)-Cullin1 complex, leading to inhibition of autophagy and receptor endocytosis. Furthermore, we show that the expression of FBXL20 is regulated by p53-dependent transcription. Our study provides a molecular pathway by which DNA damage regulates Vps34 complexes and its downstream mechanisms, including autophagy and receptor endocytosis, through SCF (Skp1-Cul1-F-box)-mediated ubiquitination and degradation. Since the expression of FBXL20 is regulated by p53-dependent transcription, the control of Vps34 ubiquitination and proteasomal degradation by FBXL20 and the associated SCF complex expression provides a novel checkpoint for p53 to regulate autophagy and receptor degradation in DNA damage response.

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The Tumor Suppressor, p53, Contributes to Radiosensitivity of Lung Cancer Cells by Regulating Autophagy and Apoptosis

Cited by 41 publications

References 22 publications

A novel cytostatic form of autophagy in sensitization of non-small cell lung cancer cells to radiation by vitamin D and the vitamin D analog, EB 1089

A novel cytostatic form of autophagy in sensitization of non-small cell lung cancer cells to radiation by vitamin D and the vitamin D analog, EB 1089

Rapamycin‐induced autophagy sensitizes A549 cells to radiation associated with DNA damage repair inhibition

FBXL20-mediated Vps34 ubiquitination as a p53 controlled checkpoint in regulating autophagy and receptor degradation

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