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Objective:To investigate the relationship between the expression level of lymphocyte enhancer-binding factor 1(LEF1) and CTNNB1 and the cycle arrest, apoptosis and radiation resistance of esophageal cancer cells and unravel the related mechanisms.Methods:Recombinantplasmids and empty plasmids expressing LEF1 and CTNNB1were constructed and transfected into esophageal cancer cells. RT-PCR assay was used to detect the transfection efficiency of the plasmids. Clone formation assay, CCK8 assay, cell cycle test by flow cytometry, apoptosis test by flow cytometry and Western blot were performed to detect the differences in theradioresistance, proliferation, cell cycle and apoptosis of esophageal cancer cells before and after transfection.Results:The survival rate of clonal colony cells in the pGEX-LEF1+ pCMV6-CTNNB1 group was significantly better than those in other groups ( P<0.05). The proliferation of clonal colony cellsat 72 h, 96 h and 120 h in the pGEX-LEF1+ pCMV6-CTNNB1 group was significantly better than those in the pGEX+ pCMV6, pGEX-LEF1+ pCMV6 and pCMV6-CTNNB1+ pGEX groups (all P<0.05). The percentage of G 2 phase arrest cells in the pGEX-LEF1+ pCMV6-CTNNB1 group was significantly higher than those in the other groups (all P<0.05). The apoptosis rate of esophageal cancer cells in the pGEX-LEF1+ pCMV6-CTNNB1 group was significantly lower compared with those in the pGEX+ pCMV6, pGEX-LEF1+ pCMV6 and pCMV6-CTNNB1+ pGEX groups (all P<0.05). The expression levels of Bax and Caspase 3 proteins in the pGEX-LEF1+ pCMV6-CTNNB1 group were significantly lower than those in the pGEX+ pCMV6, pGEX-LEF1+ pCMV6 and pCMV6-CTNNB1+ pGEX groups (all P<0.05). The expression level of Bcl-2 protein in the pGEX-LEF1+ pCMV6-CTNNB1 group was significantly higher compared with those in the other groups (all P<0.05). Conclusion:LEF1 and CTNNB1 can regulate the proliferation and G 2 phase arrest of esophageal cancer cells after radiation intervention by mediating the Wnt signaling pathway, and improve the radiation resistance of esophageal cancer cells by inhibiting cell apoptosis.
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Objective:The purpose of this study was to investigate the expression and role of N-myc downstream regulatory gene 2 (NDRG2) in radiation resistance of bladder cancer cells.Methods:T24 cells were cultured in vitro and irradiated with different doses of X-ray (0, 2, 4, 8, 10 and 20 Gy). The best dose of X-ray was selected for subsequent treatment. The radioresistant BCa cell line T24/R was established. The cytotoxicity of T24/R cells was detected by counting kit-8 (CCK-8) method. The proliferation and invasion ability of T24/R cells and T24 cells were detected by flow cytometry and transwell, respectively. Western blot was used to detect the expression of epithelial mesenchymal transition (EMT) related proteins. The survival rate of T24/R group (control group) and T24/R-NDRG 2 group was detected, and the migration ability of T24/R-NDRG 2 cells was detected after 2 Gy treatment. Results:The cell viability was inhibited significantly when the dose of X-ray was ≥2 Gy X-ray, so 2 Gy X-ray irradiation was chosen as the best condition for BCa cytotoxicity and T24/R radiation resistance cell line was successfully established; Apoptosis test showed that the number of S-phase cells was increased in T24/R group, and the proportion of S-phase cells in T24/R vs T24 was (26.49±4.5)% vs (14±2.6)% ( P<0.05); Transwell test showed that T24/R cells showed stronger migration ability than control group ( P<0.05), but there was no significant difference in EMT related protein expression between the two groups ( P>0.05). Overexpression of NDRG2 can significantly decreased the activity and migration ability of radiation-resistant T24/R cells ( P<0.05) when the radiation dose was gradually increasing in both groups. Conclusions:The radiation resistance of BCa cells is one of the causes of local tumor recurrence. Up-regulation of NDRG2 expression can inhibit the radiation resistance of T24 cells, so it can be used as a candidate for treatment of radiation-resistant BCa patients.
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Objective To investigate the effect of exosomes secreted from human lung adenocarcinoma A549 cells under hypoxic or normoxic conditions on the radiosensitivity and invasiveness of normoxia cells.Methods A549 cells were cultured in hypoxic (1％ O2) and normoxic (21％ O2) conditions,respectively.The exosomes (N-EXO and H-EXO) secreted from normoxic or hypoxic A549 cells were collected by ultracentrifugation and its number was measured using a NanoSight detector.The appearance and size distribution of exosomes were observed by a scanning electron microscopy.The exosomal marker protein CD63 was measured by Western blot.The proliferation of cells exposed to X-rays under hypoxic or normoxic conditions were detected by CCK8 assay.The cell uptake situation of exosomes labeled with PKH67 was observed by a fluorescence microscopy.Cell migration and invasiveness were detected by a cell scratch test and transwell assay.The expression of matrix metalloproteinase 2 (MMP2) and MMP9 was detected by ELISA.Cellular radioresistance effect of exosomes was evaluated by a colony formation assay.Results The NanoSight measurement showed the number of exosomes in cell culture medium was increased after hypoxia treatment.The H-EXO and N-EXO showed typical ring cake shape.The size distribution of H-EXO was mainly between 30 nm and 200 nm,smaller than that of N-EXO (50-220 nm).Western blot assay showed that CD63 was expressed in both H-EXO and N-EXO.At 4 and 6 days after 2 Gy X-rays irradiation,cell proliferation rate of hypoxia A549 cells was significantly higher than that of normoxia cells.The green fluorescent marker of exosomes,PKH67,was distributed inside of the cell.Cell scratch test showed that the width of H-EXO group was much smaller than that of N-EXO group at 12,24 and 48 hours after exosomes treatment (t =2.96,6.76,3.35,P ＜ 0.05).Transwell assay showed that the number of transmembrane cells in the H-EXO group was more than that in the N-EXO group and the control group (t =4.84,7.88,P ＜ 0.O1).The expression levels of MMP2 (t =4.70,3.21,P＜0.05) and MMP9 (t =5.61,3.76,P＜0.05) in the supernatant of H-EXO group were significantly higher than those in the control and N-EXO groups.Cell survival assay showed that the D0 values of control,N-EXO and H-EXO group were 2.614,2.552 and 4.50 respectively,indicating that H-EXO could enhance radioresistance of A549 cells significantly.Conclusions This study finds that the number of exosomes released from A549 cells was increased under hypoxic condition but its size becomes smaller than that under normoxia.Hypoxic exosomes can promote the migration of normoxia cells andenhance cell radioresistance as well.
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Objective To screen radiotherapy resistance related microRNAs (miRNAs) in breast cancer and provide experimental basis for basic researches and clinical solutions of radiotherapy resistance in breast cancer patients.Methods The miRNA microarray dataset GSE107743 related to breast cancer radiotherapy patients was downloaded from the Gene Expression Omnibus (GEO).The GEO2R analysis tool was used to screen differentially expressed miRNAs in patients with local recurrence after radiotherapy.The target genes of differentially expressed miRNAs were predicted by the mirDIP database.GO enrichment analysis and KEGG pathway analysis on the target genes were performed by DAVID dataset.Finally,differential expression verification was performed in human breast cancer cell line MCF-7 by real-time fluorescent quantitative PCR.Results A total of 9 differentially expressed miRNAs related to radiotherapy resistance were screened by the GEO2R analysis tool,in which three miRNAs (hsa-miR-600,hsa-miR-525-3p and hsa-miR-591) were up-regulated and 6 miRNAs (hsa-miR-488-5p,hsa-miR-582-3p,hsa-miR-520h,hsa-miR-488-3p,hsa-miR-744-3p and hsa-miR-103b) were down-regulated.Target gene prediction results showed that there were 134 potential target genes in these nine differentially expressed miRNAs.These target genes were significantly enriched in related biological processes such as apoptosis and stem cell differentiation (all P＜0.05) and signal transduction pathways such as transforming growth factor-β and phosphatidylinositol 3-kinase-protein kinase B signaling pathway (all P＜0.05).The results of real-time PCR showed that the differential expression of six miRNAs,i.e.hsa-miR-600,hsa-miR-525-3p,hsa-miR-591,hsa-miR488-5p,hsa-miR-582-3p and hsa-miR-520h,was detected in the MCF-7 cells irradiated by 5 Gy 137Cs γ-rays,and this result was consistent with the results of GEO2R analysis.Conclusion The differentially expressed miRNAs screened from clinical samples of breast cancer patients with local recurrence using bioinformatics may be closely associated with the radiotherapy resistance of these patients.These miRNAs are expected to become new biomarkers for the therapy of radiotherapy resistance.
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Objective To investigate the effect of PDLIM4 (PDZ and LIM domain 4) gene on the prognosis and radiosensitivity of glioma. Methods The differentially expressed genes were analyzed by bioinformatics technique using GSE53733 gene chip. The expression of PDLIM4 protein was detected by Western blot. The effects of PDLIM4 gene on glioma prognosis and glioma cell radiosensitivity were studied by using real-time fluorescence quantitative PCR, siRNA, MTT and cell flow cytometry assays. Results PDLIM4 gene had the most significant differential expression in the chip (logFC=1. 055897, P<0. 05). The PCR assay of 40 glioma cases in our hospital confirmed that expression of PDLIM4 showed obvious difference between high- and low-grade gliomas (t =4. 44, P <0. 05), which was correlated with the survival of patients (χ2 =5. 52, P<0. 05). Moreover, PDLIM4 gene was involved in radioresistance of glioma cells (t = 35.99, P < 0.05). Conclusions PDLIM4 gene expression level correlates with malignant degree and prognosis of glioma and also contributes to cell radioresistance.
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Objective To investigate the effect of PDLIM4 (PDZ and LIM domain 4) gene on the prognosis and radiosensitivity of glioma. Methods The differentially expressed genes were analyzed by bioinformatics technique using GSE53733 gene chip. The expression of PDLIM4 protein was detected by Western blot. The effects of PDLIM4 gene on glioma prognosis and glioma cell radiosensitivity were studied by using real-time fluorescence quantitative PCR, siRNA, MTT and cell flow cytometry assays. Results PDLIM4 gene had the most significant differential expression in the chip (logFC=1. 055897, P<0. 05). The PCR assay of 40 glioma cases in our hospital confirmed that expression of PDLIM4 showed obvious difference between high- and low-grade gliomas (t =4. 44, P <0. 05), which was correlated with the survival of patients (χ2 =5. 52, P<0. 05). Moreover, PDLIM4 gene was involved in radioresistance of glioma cells (t = 35.99, P < 0.05). Conclusions PDLIM4 gene expression level correlates with malignant degree and prognosis of glioma and also contributes to cell radioresistance.
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Benzylideneacetophenone derivative (1E)-1-(4-hydroxy-3-methoxyphenyl) hept-1-en-3-one (JC3) elicited cytotoxic effects on MDA-MB 231 human breast cancer cells-radiation resistant cells (MDA-MB 231-RR), in a dose-dependent manner, with an IC₅₀ value of 6 μM JC3. JC3-mediated apoptosis was confirmed by increase in sub-G1 cell population. JC3 disrupted the mitochondrial membrane potential, and reduced expression of anti-apoptotic B cell lymphoma-2 protein, whereas it increased expression of pro-apoptotic Bcl-2-associated X protein, leading to the cleavage of caspase-9, caspase-3 and poly (ADP-ribose) polymerase. In addition, JC3 activated mitogen-activated protein kinases, and specific inhibitors of these kinases abrogated the JC3-induced increase in apoptotic bodies. JC3 increased the level of intracellular reactive oxygen species and enhanced oxidative macromolecular damage via lipid peroxidation, protein carbonylation, and DNA strand breakage. Considering these findings, JC3 is an effective therapy against radiation-resistant human breast cancer cells.
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Humans , Apoptosis , bcl-2-Associated X Protein , Breast Neoplasms , Breast , Caspase 3 , Caspase 9 , Chalcone , DNA , Extracellular Vesicles , Lipid Peroxidation , Membrane Potential, Mitochondrial , Mitogen-Activated Protein Kinases , Oxidative Stress , Phosphotransferases , Protein Carbonylation , Reactive Oxygen SpeciesABSTRACT
Objective To study the radiation sensitive enhancement ratio (SER) of NS398 on esophageal cancer stem cells and adherent tumor cells and analyze the radioresistance related protein expressions.Methods ECA109 esophageal cancer stem cells were cultured in serum-free medium.Expression levels of cell surface maker CD44 + and CD271 + were analyzed by flow cytometry.MTT assay was used to detect cell proliferation after the treatments with NS398 and irradiation(0,4 and 8 Gy).The sensitization effects of NS398 on the parental cells and its spheroid were evaluated by clone formation assay.Western blot assay was performed to determine protein expressions.Results Serum-free medium was successfully applied to isolate the cancer stem cells with spherical properties.CD271 + in the spheroid cells was notable higher than that in the parent cells (t =3.81,P ＜ 0.05).After irradiation,the proliferation rate of parental cells was higher than that in spheroid cells.After the combination treatment of NS398 and irradiation,SF2 value of parental cells was lower than spheroid cells(t =2.91,P ＜ 0.05)and the SER of NS398 on parental cells was greater than spheroid cells.The expressions of Bmi-1,c-Myc,β-catenin and Cyclin D1 in spheroid cells were higher than those in parental cells (t =8.09,7.90,7.50,7.15,P＜0.05).Cyclin D1 expression levels under both cell situations increased after 4 Gy irradiation (t =9.74,6.67,P ＜0.05).Compared to the 4 Gy irradiation alone group,the β-catenin and Cyclin D1 expression levels in both parental cells (t =10.15,12.12,P ＜ 0.05) and spheroid cells (t =3.23,7.45,P ＜ 0.05) decreased in the combination group.Conclusions Esophageal cancer stem cells with high level of CD271 can be isolated with serum-free medium and it is radioresistant where β-catenin and its downstream proteins may be involved.
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Objective To investigate the low-dose hyper-radiosensitivity (HRS)/induced radioresistance (IRR) in A549 cells synchronized at G2 phase and the role of ATM kinase in the process.Methods Human lung adenocarcinoma cell line A549 was synchronized at G2 phase by aphidicolin.The ATM-specific activator and inhibitor,chloroquine and KU55933,were used to regulate the activity of ATM.The colony formation assay was used to evaluate cell survival.Flow cytometry was used to determine the cell cycle of radiation-exposed A549 cells synchronized at G2 phase.Immunofluorescence was used to observe the dynamics of γ-H2AX fluorescence and evaluate the efficiency of DNA repair in A549 cells synchronized at G2 phase.Western blot was used to detect the expression of phosphorylated ATM (Ser1981) and ATM.Results A549 cells synchronized at G2 phase had substantially enhanced HRS than non-synchronized cells.The dose-induced transition from HRS to 1RR was in accordance with the dose-response pattern of early G2/M checkpoint.However,with the same threshold dose,the activation of early checkpoint occurred earlier and lasted longer than normal.The activation of ATM kinase inhibited HRS and enhanced DNA repair,while the inhibition of ATM kinase enhanced HRS and hindered DNA repair.Conclusions ATM kinase-mediated early G2+M checkpoint is a molecular switch for HRS in synchronized A549 cells.Low-dose irradiation with G2-phase synchronization and ATM inhibitor can enhance the low-dose radiosensitivity.
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Objective To study the pathway of miR-221/222 in enhancing radiation resistance of glioblastoma.Methods After 2 Gy of X-ray irradiation,the expressions of miR-221/222 in U251,U87 and LN229 glioblastma cells were detected with real-time PCR.Clonogenic assay was used to measure the radiosensitivity of glioblastoma after knocking down miR-221/222.ChIP assay was used to identify the combination situation of c-jun and miR-221/222.Luciferase assay was applied to check whether PTEN was a target of miR-221/222.Western blot was used to detect the expression of relevant proteins in the glioblastoma cells after knocking down miR-221/222.The effect of miR-221/222 and irradiation on growth of glioblastoma in nude mice was also observed.Results The expression of miR-221/222 was increased by irradiation(t =5.48 ～29.21,P ＜ 0.05) and the radiosensitivity of anti-miR-221/222-transfected cells was alsoincreased(F=1 202.22,1 789.12,1 012.32,P＜0.05).MiR-221/ 222 was transcriptionally regulated by c-jun with a target of PTEN (t =13.16,P ＜ 0.05).When miR-221/222 was knocked-down,the expression of pAkt and DNA-PKcs were down-regulated while PTEN and GSK-3β were up-regulated,and the expression of Akt were not changed.Moreover,the growth of xenograft tumor was significantly inhibited by the combination treatment of anti-miR-221/222 and irradiation(F =56.36,P ＜ 0.05).Conclusions The expression of miR-221/222 in glioblastoma cells can be increased by irradiation,and the activation of Akt pathway downstream miR-221/222 could enhance the radiation resistance of glioblastoma.
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Objective To establish a radiation-resistant cell subline from a human small cell lung cancer ( SCLC) cell line NCI-H446, providing a pairing research tool for investigating mechanism of radiation tolerance and the reverse strategy in lung cancer .Methods The NCI-H446 cell was radiated repeatedly by increased dose of radiation gradually (total 7500cGy) and a radiation-resistant cell substrain was induced and selected from the survival of cells .The doubling time and cell cycle distribution of the substrain were detected by ATP kit and flow cytometry Assay respectively ;Radiation biology parameters were calculated and analyzed by cell survival curve fitting from multi -target model, SF=1-(1-e-D/D0) N.Results Comparing with the control , The resistant substrain radiobiology parameter values were D 0 ( 1.9673, 2.2756), N(1.0016,2.6008), Dq (0.6783,1.6860)and SF2(0.3623,0.7134) respectively.Cell morphology is more slender and has more tentacles .The SF2 value of radiation-resistant subline is 1.97 times more than that of wild cell line . The proportion of radiation-resistant cells in G2/M-phase was down to 7.84%, compared with the 18.52%of wild cells. Conclusions A radiation-resistant SCLC subline NCI-H446-R is established and may be a useful tool for studying resistant to radiation of SCLC in the future .
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Objective To investigate the effect of COX￣2 inhibitor celecoxib on radiosensitity of irradiation￣resistant cell line CNE￣2R of nasopharyngeal carcinoma and the potential mechanism. Methods Via exposing to a series of X￣ray (2, 4, 6, 8 Gy, 3 times for each dose), radio￣resistant cell subline CNE￣2R was established from human nasopharyngeal carcinoma cell CNE￣2.Radiosensitivity was detected by clone formation assay.CNE￣2R and CNE￣2 cell lines were exposed to 25, 50, 75 μmol.L-1 celecoxib, respectively.Western blotting was used to detect the protein expression of COX￣2.Clone formation assay was performed to measure the survival fraction of CNE￣2 and CNE￣2R after radiotherapy alone or radiotherapy combined with 30 μmol.L-1 celecoxib treatment.Flow cytometry was used to measure influence of radiotherapy alone or radiotherapy combined with 30 μmol.L￣1celecoxib treatment on cell apoptosis.Number of residual γ￣H2AX foci was observed by immunofluorescence assay. Results The colony forming assay demonstrated that the values of SF2, D0 , Dq , and N of CNE￣2R cell subline [(0.81±0.05), (2.15±0.07) Gy, (2.94±0.08) Gy, (3.91±0.07), respectively] was significant higher than those of CNE￣2 cell line [(0.61±0.08), (1.47±0.06) Gy, (1. 68 ± 0. 10) Gy, (3. 13 ± 0. 05), respectively]. The expression of COX￣2 protein was significantly downregulated with increasing celecoxib concentration.Surviving fraction was decreased in both CNE￣2 and CNE￣2R cell lines after irradiation.After radiotherapy combined with celecoxib, apoptosis rates of CNE￣2 and CNE￣2R cell lines [(13.10±0.63)%, (5.30±0.75)%] were higher than those of the corresponding control groups [(4.90±0.71)%, (1.82±0.82)%].Celecoxib increased radiosensitivity in nasopharyngeal carcinoma CNE￣2R and CNE￣2 cell lines.The number of residual γ￣H2AX foci after irradiation was increased by celecoxib pretreatment.The difference was statistically significant (P<0.05). Conclusion Celecoxib can enhance radiosensitivity of radio￣resistant cell subline CNE￣2R of human nasopharyngeal carcinoma in vitro.
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Chemotherapy, molecular targeted therapy, and hormonal therapy are essential components of medical oncology. Al-though cancer patients significantly benefit from the emergence of various new anticancer drugs, none of these treatments can directly address drug resistance. Radiation therapy is one of the three conventional cancer treatment methods. Nearly two-thirds of cancer pa-tients accept radiation therapy during treatment. However, radiation resistance is a significant barrier affecting the therapeutic effect of this procedure. Epithelial–mesenchymal transition (EMT) is a biologic process that enables a polarized epithelial cell to undergo multi-ple biochemical changes. These changes enable the cell to assume the functions of a mesenchymal cell phenotype. These functions have been extensively studied and are related to embryogenesis, tumor invasiveness, and metastasis. In recent years, increasing evidence sug-gests that EMT is closely linked with tumor treatment resistance. The study of the relation between EMT and tumor treatment resistance is expected to contribute to the prevention of drug resistance and radiation resistance and thus improve treatment efficacy to provide benefit to cancer patients. This article explores this issue.
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Objective To construct the eukaryotic expression vector of pprI gene from Deinococcus radiodurans R1 and investigate its radioresistant effects in eukaryotic cells.Methods A recombinant vector pEGFP-c1-pprI was constructed by DNA recombinant technique.The empty vector pEGFP-c1 and the pEGFP-c1-pprI were transferred into human lung epithelial cells Beas-2B by LipofectamineTM 2000,respectively.Then the infected cells were screened in order to develop a cell line with stable expression of pprI gene.Cell survival rate was tested by clone-forming assay.Cell cycle distribution and apoptosis were detected by a flow cytometry.The fluorescence intensity of reactive oxygen species (ROS) was observed by a fluorescent microscope.γ-H2AX foci in the irradiated cell was detected by immunofluorescence.Results The eukaryotic expression plasmid of pprI prokaryotic gene was constructed and PprI fusion protein was expressed in human lung epithelial cells successfully,and the cell line (2BG) with a stable pprI gene expression was established.After irradiation,the cell survival fraction of 2BG cells was significantly higher than Beas-2B cells so that the value of D0 、Dq and N of the survival curve were increased.Moreover,the fluorescence intensity of ROS and the number of γ-H2AX foci in 2BG cells were also lower than those of B eas-2B cells(F =16.73,19.47,6.94,P ＜ 0.05).Between these two cell lines,the apoptosis rate and cell cycle G2 arrest also had significant difference (F =139.73,237.92,P ＜ 0.05).Conclusions The pprI gene from Deinococcus radiodurans RI can be stably expressed in the eukaryotic cells and it allows the transferred cells to have a radioresistant function.
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Objective To elucidate the mechanism of radiation resistant effect of LyGDI on NSCLC A549 cells.Methods A549 and H460 cells were irradiated with X-rays of 0,2,4 and 6 Gy.The clone-forming assay was used to detect cell survival and radiosensitivity.The expressions of LyGDI and COX-2 (Cyclooxygenase-2),a key radiosensitivity-related protein,were detected using Western blot.The miR-34 families were analyzed with RT-PCR.50 nmol/L mature miR-34c was transfected into A549 cells.Results The expression levels of LyGDI and COX-2 were much higher in radioresistive A549 cells than that in H460 cells.While the expression of miR-34a was quite low and miR-34b/c was hardly found in both NSCLC cells.Transfection of miR-34c into A549 cells strongly enhanced X-ray induced apoptosis by inhibiting the activations of LyGDI,COX-2,Bcl-2 and p21.Conclusions Up-regulation of LyGDI could induce COX-2 expression.The low expression of miR-34 family might be responsible for the radiation resistance of NSCLC cells.
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Radiation therapy is a key modality in the management of a majority of patients diagnosed with cancer. To know prognostic markers related radiation response can aid in refining our treatment strategies and improving outcomes. With the help of powerful molecular tools, a substantial amount of research efforts have been devoted to identifying molecular markers for prognostic and therapeutic strategies. In this review, we summarize recent research efforts evaluating molecular markers or pathways as they relate to radiation resistance of solid tumors. With respect to radiation response, literatures regarding molecules related to growth factors, apoptosis, cell cycle, angiogenesis, heat shock protein, and histone deacetylase will be reviewed. We also introduce new molecular agents enhancing radiation response which are available in clinic. In addition, we discuss current clinical trials using these molecular agents on cervical cancer.
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Humans , Apoptosis , Cell Cycle , Heat-Shock Proteins , Histone Deacetylases , Intercellular Signaling Peptides and Proteins , Radiation Tolerance , Uterine Cervical NeoplasmsABSTRACT
OBJECTIVE: The aim of this study was to investigate the association of phosphorylated AKT (pAKT) expression and radiation resistance in cervical cancer. METHODS: A retrospective review was made of the records of 25 women who received primary radiation therapy due to locally advanced cervical cancer (LACC) with FIGO stage IIB-IVA. Nine patients regarded as radiation resistant developed local recurrences with a median progression free interval of 10 months. Sixteen patients did not show local recurrences, and were regarded as a radiation sensitive group. Using pretreatment paraffin-embedded tissues, we evaluated pAKT expression by immunohistochemistry. RESULTS: A significant association was found between the level of pAKT expression and local recurrence. Immunohistochemical staining for pAKT was significantly more frequent in the radiation resistant than in the radiation sensitive group (p=0.007). The mean progression free survival (PFS) was 84 months for patients with pAKT negative staining (17 cases) and 44 months for patients with pAKT positive expression (8 cases)(p=0.015). CONCLUSION: These results suggest that signaling from PI3K/pAKT can lead to radiation resistance in LACC.