Targeted inhibition of mammalian target of rapamycin (mTOR) enhances radiosensitivity in pancreatic carcinoma cells

Dai, Zhijun; Gao, Jie; Kang, Huafeng; Ma, Yihui; Ma, Xiaolong; Lu, Wang-Feng; Lin, Shuai; Ma, Hongbing; Wang, Xijing; Wang, Wenying

doi:10.2147/dddt.s42390

Cited by 26 publications

(14 citation statements)

References 53 publications

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“…Rapamycin‐induced autophagy in MCF‐7 breast cancer cells delayed the attendance of Rad51 and breast cancer 1 (BRCA1) in DSBs upon radiotherapy, leading to the accumulation of DSBs and cell death . Similarly, the sensitivity of pancreatic carcinoma cell PC‐2 to radiotherapy was significantly enhanced post‐rapamycin treatments, and the upregulation of autophagy mediator Beclin‐1 sensitized lung cancer cells to irradiation , . These findings suggest that autophagy may play an important role in cancer radiotherapy.…”

Section: Introductionmentioning

confidence: 89%

“…The experiment was performed as previously described . In brief, A549 cells were seeded into wells of a six‐well plate with a concentration of 200 cells per well.…”

Section: Methodsmentioning

confidence: 99%

“…The experiment was performed as previously described. 14 In brief, A549 cells were seeded into wells of a six-well plate with a concentration of 200 cells per well. After overnight incubation, cells were treated with 100 nmol/L of rapamycin for 24 hours and/or exposed to 4 Gy of radiation.…”

Section: Clonogenic Survival Assaymentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 89%

“…The experiment was performed as previously described . In brief, A549 cells were seeded into wells of a six‐well plate with a concentration of 200 cells per well.…”

Section: Methodsmentioning

confidence: 99%

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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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“…The blockade of the mTORC1 can activate the ULK1 complex and promote the interaction with the PtdIns3K complex which is necessary for the formation of new autophagosomes (47). Several studies have reported on the positive effects of mTOR inhibitor on sensitizing cancers to radiation therapy and chemotherapy in lung cancer, pancreatic carcinoma cells and esophageal carcinoma cells (48)(49)(50)(51).…”

Section: Dna Damage Repair and Autophagymentioning

confidence: 99%

Crosstalk between autophagy and intracellular radiation response (Review)

Wang

Huang

et al. 2016

International Journal of Oncology

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Abstract. Autophagy induced by radiation is critical to cell fate decision. Evidence now sheds light on the importance of autophagy induced by cancer radiotherapy. Traditional view considers radiation can directly or indirectly damage DNA which can activate DNA damage the repair signaling pathway, a large number of proteins participating in DNA damage repair signaling pathway such as p53, ATM, PARP1, FOXO3a, mTOR and SIRT1 involved in autophagy regulation. However, emerging recent evidence suggests radiation can also cause injury to extranuclear targets such as plasma membrane, mitochondria and endoplasmic reticulum (ER) and induce accumulation of ceramide, ROS, and Ca 2+ concentration which activate many signaling pathways to modulate autophagy. Herein we review the role of autophagy in radiation therapy and the potent intracellular autophagic triggers induced by radiation. We aim to provide a more theoretical basis of radiation-induced autophagy, and provide novel targets for developing cytotoxic drugs to increase radiosensitivity. Contents1. Introduction 2. The role of autophagy in radiotherapy 3. DNA damage repair and autophagy 4. Mitochondrial damage and autophagy 5. ER stress and autophagy 6. ROS and autophagy 7. Ceramide and autophagy 8. Ca 2+ and autophagy 9. Targeting autophagy for radiotherapy 10. Conclusion IntroductionRadiotherapy is an effective strategy for the treatment of many kinds of cancer to kill or control the malignant tumor cells. However, its benefits have been limited due to radiation resistance. It is imperative to identify new targets and develop cytotoxic drugs to increase radiosensitivity. Radiosensitization has traditionally been performed with agents known to induce apoptosis. However, recent studies demonstrate autophagy induced by radiation also plays an important role in cancer Crosstalk between autophagy and intracellular radiation response (Review)

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“…These anti-cancer effects of EGCG on pancreatic cancer cells are mediated through the up-regulation of PTEN expression and the down-regulation of phospho-Akt and phospho-mTOR, suggesting the molecular regulation of EGCG on Akt/mTOR signaling. Importantly, the targeted inhibition of mTOR signaling has been found to enhance radiosensitivity in pancreatic carcinoma cells (109), suggesting that the suppression of mTOR signaling by nutraceuticals such as metformin and EGCG could potentiate the anti-cancer activity of radiation therapy for achieving better treatment outcomes in patients diagnosed with pancreatic cancer.…”

Section: Nutraceuticals For Pancreatic Cancer Treatmentmentioning

confidence: 99%

The Role of Nutraceuticals in Pancreatic Cancer Prevention and Therapy

Li¹,

Go²,

Sarkar³

2015

Pancreas

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Pancreatic cancer is one of the most aggressive malignancies in US adults. The experimental studies have found that antioxidant nutrients could reduce oxidative DNA damage, suggesting that these antioxidants may protect against pancreatic carcinogenesis. Several epidemiologic studies showed that dietary intake of antioxidants was inversely associated with the risk of pancreatic cancer, demonstrating the inhibitory effects of antioxidants on pancreatic carcinogenesis. Moreover, nutraceuticals, the anti-cancer agents from diet or natural plants, have been found to inhibit the development and progression of pancreatic cancer through the regulation of cellular signaling pathways. Importantly, nutraceuticals also up-regulate the expression of tumor suppressive miRNAs and down-regulate the expression of oncogenic miRNAs, leading to the inhibition of pancreatic cancer cell growth and pancreatic Cancer Stem Cell (CSC) self-renewal through modulation of cellular signaling network. Furthermore, nutraceuticals also regulate epigenetically deregulated DNAs and miRNAs, leading to the normalization of altered cellular signaling in pancreatic cancer cells. Therefore, nutraceuticals could have much broader use in the prevention and/or treatment of pancreatic cancer in combination with conventional chemotherapeutics. However, more in vitro mechanistic experiments, in vivo animal studies, and clinical trials are needed to realize the true value of nutraceuticals in the prevention and/or treatment of pancreatic cancer.

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Targeted inhibition of mammalian target of rapamycin (mTOR) enhances radiosensitivity in pancreatic carcinoma cells

Cited by 26 publications

References 53 publications

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

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

Crosstalk between autophagy and intracellular radiation response (Review)

The Role of Nutraceuticals in Pancreatic Cancer Prevention and Therapy

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