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(Mtor) Enhances Radiosensitivity in Pancreatic Carcinoma Cells

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(Mtor) Enhances Radiosensitivity in Pancreatic Carcinoma Cells Drug Design, Development and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Targeted inhibition of mammalian target of rapamycin (mTOR) enhances radiosensitivity in pancreatic carcinoma cells Zhi-Jun Dai1,* Abstract: The mammalian target of rapamycin (mTOR) is a protein kinase that regulates protein Jie Gao2,* translation, cell growth, and apoptosis. Rapamycin (RPM), a specific inhibitor of mTOR, exhibits Hua-Feng Kang1,* potent and broad in vitro and in vivo antitumor activity against leukemia, breast cancer, and Yu-Guang Ma1 melanoma. Recent studies showing that RPM sensitizes cancers to chemotherapy and radiation Xiao-Bin Ma1 therapy have attracted considerable attention. This study aimed to examine the radiosensitizing Wang-Feng Lu1 effect of RPM in vitro, as well as its mechanism of action. 3-(4,5-Dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide (MTT) assay and colony formation assay showed that Shuai Lin1 10 nmol/L to 15 nmol/L of RPM had a radiosensitizing effects on pancreatic carcinoma cells Hong-Bing Ma1 in vitro. Furthermore, a low dose of RPM induced autophagy and reduced the number of S-phase Xi-Jing Wang1 For personal use only. cells. When radiation treatment was combined with RPM, the PC-2 cell cycle arrested in the 3 Wen-Ying Wu G2/M phase of the cell cycle. Complementary DNA (cDNA) microarray and reverse transcription 1Department of Oncology, polymerase chain reaction (RT-PCR) revealed that the expression of DDB1, RAD51, and 2 Department of Nephrology, XRCC5 were downregulated, whereas the expression of PCNA and ABCC4 were upregulated 3Department of Pharmacology, Second Affiliated Hospital, Medical in PC-2 cells. The results demonstrated that RPM effectively enhanced the radiosensitivity of School of Xi’an Jiaotong University, pancreatic carcinoma cells. Xi’an, People’s Republic of China Keywords: radiation; pancreatic carcinoma; mTOR; rapamycin *These authors contributed equally to this work Introduction Pancreatic cancer is the most lethal of the solid tumors and the fourth leading cause of cancer-related death in North America.1,2 The incidence of pancreatic cancer has been gradually increasing, even though the incidence of other common cancers has Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 23-Dec-2018 declined.3 About 80% to 85% of patients with pancreatic cancer present with locally advanced or metastatic disease that precludes curative resection and have a poor prognosis.1,3 Despite developments in detection and treatment, the 5-year survival rate of pancreatic cancer is only about 4%.3 Radiotherapy allows tumor control through the cytotoxic action of ionizing radiation. Radiotherapy is used frequently in the management of multiple tumor types, including locally advanced pancreatic cancer. Although modern technologies permit precise radiation delivery to the tumor mass, while minimizing the exposure Correspondence: Zhi-Jun Dai; Xi-Jing Wang; Department of Oncology, Second of the surrounding healthy tissues, the efficacy of radiotherapy remains limited by Affiliated Hospital, Medical School of the intrinsic or acquired radioresistance of tumors. Enhancing tumor radiosensitivity Xi’an Jiaotong University, 710004 Xi’an, could reduce the amount of radiation required for definitive treatment and improve People’s Republic of China Tel +86 29 8767 9226 clinical outcome. The recent interest in targeting the components of signaling Fax +86 29 8767 9282 pathways prompts an urgent search for agents that enhance the sensitivity of tumor Email [email protected]; [email protected] cells to irradiation. submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2013:7 149–159 149 Dovepress © 2013 Dai et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article http://dx.doi.org/10.2147/DDDT.S42390 which permits unrestricted noncommercial use, provided the original work is properly cited. Powered by TCPDF (www.tcpdf.org) 1 / 1 Dai et al Dovepress The signaling pathways that activate mammalian target of MTT assay rapamycin (mTOR) are altered in many human cancers, and The viability of pancreatic cancer cells was assessed using these alterations are associated with prognosis and treatment an MTT dye reduction assay (Sigma-Aldrich), which was response.4 Inhibiting mTOR has been found to enhance the conducted as described in a previous work.21 After irradiation, cytotoxicity of DNA-damaging agents in several cancer the cells were seeded in a 96-well plate at a density of cells.5–7 Rapamycin (RPM) is a lipophilic macrolide antibiotic 1 × 104 cells/well, cultured for 12 hours, then treated with initially developed as a fungicide and immunosuppressant.8 different concentration (10, 20, 30, 40, and 50 µmol/L) Previous studies have reported that RPM has antiproliferative RPM for 0–96 hours. At the end of the treatment, MTT, effects on some tumors.9–15 RPM also acts as a specific 50 µg/10 µL, was added, and the cells were incubated for mTOR inhibitor. In several, but not all cancer cell lines, another 4 hours. Dimethyl sulfoxide (DMSO), 200 µL, RPMs (RPM and its derivatives) increase the irradiation was added to each well after removal of the supernatant. cytotoxicity in vitro through multiple mechanisms, including After shaking the plate for 10 minutes, cell viability was the autophagy pathway.16–19 RPMs may also increase the assessed by measuring the absorbance at 490 nm, using effects of radiotherapy in tumor xenograft models.20 This an enzyme-labeling instrument (EX-800 type, Bio-Tek, study aimed to examine the radiosensitizing effect of RPM Winooski, VT, USA); all measurements were performed four on pancreatic cancer in vitro and its molecular mechanism. times. A cell growth curve was completed, using time as the abscissa and absorbance value (A value) (mean ± standard Material and methods deviation [SD]) as the ordinate. Reagents The reagents used in our research were: tetal bovine serum Colony formation assay (Gibco® FBS; Life Technologies, Carlsbad, CA, USA); A colony formation assay was applied for measurement of the Roswell Park Memorial Institute (RPMI) medium (Gibco clonogenic cell survival, as described in a previous work.22 RPMI 1640; Life Technologies); 3-(4,5-Dimethylthiazol-2- After the treatment with radiation, the cells were plated into For personal use only. yl)-2,5-diphenyltetrazolium bromide (MTT) (Sigma-Aldrich, 60 mm petri dishes, with standard culture media. After 2 weeks, St Louis, MO, USA); reverse transcription polymerase chain the cells were fixed with 4% formaldehyde, stained with crystal reaction (RT-PCR) kit (catalog #sc-8319 Ampliqon A/S, violet, and colonies containing more than 50 cells were counted Odense, Denmark); TRIzol® Reagent (Life Technologies); and normalized to their corresponding nonirradiated control. mTOR monoclonal antibody (Santa Cruz Biotechnology The surviving fraction for a given treatment was calculated Inc, Dallas, TX, USA); Rapamycin (RPM) (Sigma-Aldrich); as the plating efficiency of the irradiated samples relative monodansylcadaverine (MDC) (Sigma-Aldrich). to that of the sham irradiated ones. Each point on survival curves represents the mean surviving fraction from at least Cell culture and irradiation three independent experiments. The multitarget click model Human pancreatic cancer cell lines, PC-2 and PANC-1 were in GraphPad Prism 5.0 (GraphPad Software Inc, San Diego, obtained from the Shanghai Institute of Cell Biology, Chinese CA, USA) was used to fit the cell survival curves. Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 23-Dec-2018 Academy of Sciences (Shanghai, People’s Republic of The surviving fractions (SF) were calculated as follows: China). Cells were cultured in RPMI 1640 maximal medium SF = number of clones formed after irradiation of the cells/ containing 10% inactivated (56°C, 30 minutes) fetal bovine the number of cells inoculated × cell planting rate (the 0 Gy serum, 1 × 105 U/L penicillin, and 100 mg/L streptomycin, in group was calculated as the planting rate). a humidified atmosphere with 5% CO2 incubator at 37°C. The radiosensitive enhancement ratio = SF of the control The PC-2 and PANC-1 cells were then treated with 2, 4, group/SF2 of the drug-treated group. 6, 8, and 10 Gy of X-ray irradiation, using a Varian Clinac® 2100EX linear accelerator (Varian Medical Systems Inc, Palo MDC staining of autophagic vacuoles Alto, CA, USA), at a dose rate of 400 cGy/min. The distance MDC staining of autophagic vacuoles was performed for the between the cells and the radiation source was maintained autophagy analysis, as described in a previous work.23 The at 1 meter. After irradiation, the medium was immediately PC-2 cells were divided into a control group, a 10 nmol/L replaced with fresh medium. The dishes were then returned to RPM group, and a 15 nmol/L RPM group. The cells were the incubator for further culture, and the cells were harvested incubated for 48 hours on coverslips. Autophagic vacuoles at 0, 24, 48, 72, 96, and 120 hours. were labeled with 0.05 mmol/L MDC in phosphate-buffered 150 submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2013:7 Dovepress Powered by TCPDF (www.tcpdf.org) 1 / 1 Dovepress Inhibition of mTOR enhances radiosensitivity in pancreatic carcinoma saline (PBS) at 37°C for 10 minutes. Then, the cells were Microarray Scanner and Feature Extraction 9.5.3 software washed three times with PBS. The autophagic vacuoles (Agilent Technologies Inc). Total gene signal normalization in the PC-2 cells were observed under a fluorescence at the 75th percentile of raw signal values and baseline microscope (Olympus BX60; Olympus Corp, Tokyo, Japan). transformation at the median of all samples was performed The fluorescence intensity of MDC was measured at an using the GeneSpring® software 10.1 (Agilent Technologies excitation wavelength of 380 nm, emission wavelength of Inc), following the instructions of the manufacturer.
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