Disruption of Chromosomal Architecture of cox2 Locus Sensitizes Lung Cancer Cells to Radiotherapy.
Ontology highlight
ABSTRACT:
SUBMITTER: Sun Y
PROVIDER: S-EPMC6171098 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Genetic lesions that activate KRAS account for ∼30% of the 1.6 million annual cases of lung cancer. Despite clinical need, KRAS is still undruggable using traditional small-molecule drugs/inhibitors. When oncogenic Kras is suppressed by RNA interference, tumors initially regress but eventually recur and proliferate despite suppression of Kras Here, we show that tumor cells can survive knockout of oncogenic Kras, indicating the existence of Kras-independent survival pathways. Thus, even if clinical KRAS inhibitors were available, resistance would remain an obstacle to treatment. Kras-independent cancer cells exhibit decreased colony formation in vitro but retain the ability to form tumors in mice. Comparing the transcriptomes of oncogenic Kras cells and Kras knockout cells, we identified 603 genes that were specifically up-regulated in Kras knockout cells, including the Fas gene, which encodes a cell surface death receptor involved in physiological regulation of apoptosis. Antibodies recognizing Fas receptor efficiently induced apoptosis of Kras knockout cells but not oncogenic Kras-expressing cells. Increased Fas expression in Kras knockout cells was attributed to decreased association of repressive epigenetic marks at the Fas promoter. Concordant with this observation, treating oncogenic Kras cells with histone deacetylase inhibitor and Fas-activating antibody efficiently induced apoptosis, thus bypassing the need to inhibit Kras. Our results suggest that activation of Fas could be exploited as an Achilles' heel in tumors initiated by oncogenic Kras.
| S-EPMC5389295 | biostudies-literature
Project description:Although radiotherapy is often used to treat localized disease and for palliative care in prostate cancer patients, novel methods are required to improve the sensitivity of aggressive disease to ionizing radiation. AMP-activated protein kinase (AMPK) is an energy sensor which regulates proliferation, aggressiveness and survival of cancer cells. We assessed the ability of the AMPK activator 5-aminoimidazole-4-carboxamide-1-?-D-ribofuranoside (AICAR) to sensitize prostate cancer cells to radiation. Prostate cancer cell lines LNCaP and PC3 were treated with X-rays and AICAR then assessed for clonogenic survival, spheroid growth delay, cell cycle progression, and AMPK and p53 activity. AICAR synergistically enhanced the clonogenic killing capacity, spheroid growth inhibition and pro-apoptotic effect of X-rays. The mechanism of radiosensitization appeared to involve cell cycle regulation, but not oxidative stress. Moreover, it was not dependent on p53 status. Treatment of PC3 cells with a fatty acid synthase inhibitor further enhanced clonogenic killing of the combination of X-rays and AICAR, whereas mTOR inhibition caused no additional enhancement. These results indicate that interference with metabolic signalling pathways which protect cells against irradiation have the potential to enhance radiotherapy. Activation of AMPK in combination with radiotherapy has the potential to target metabolically active and aggressive tumors which are currently untreatable.
| S-EPMC6366825 | biostudies-literature
Project description:MicroRNAs (miRNAs) are believed to be resistant against radiotherapy in certain types of cancers. The aim of our study was to determine the clinical application of miRNAs in non-small cell lung cancer (NSCLC). Sixty NSCLC tissue samples and adjacent histologically normal tissues were obtained for miRNAs microarray analysis and validated by RT-qPCR. Correlation between miRNA expression level and clinicopathological features was evaluated. Our study examined the influence of changed miRNA expression on the damaged DNA and its associated radio sensitivity. Luciferase assay was performed to determine potential effects on the targeted gene. Our study identified fifteen altered miRNAs in which miR-328-3p was down regulated in NSCLC tumour tissue as compared to normal tissues. Down-expression of miR-328-3p was positively associated with an enhanced lymph node metastasis, advanced clinical stage and a shortened survival rate. miR-328-3p expression was decreased in A549 cells compared to other NSCLC cell lines. Up-regulation of miR-328-3p demonstrated a survival inhibition effect in A549 and restored NSCLC cells' sensitivity to radio therapy. An increased miR-328-3p expression promoted irradiation-induced DNA damage in cells. ?-H2AX was identified as the direct target of miR-328-3p. Over-expressed miR-328-3p can improve the radiosensitvity of cells by altering the DNA damage/repair signalling pathways in NSCLC.
| S-EPMC4987701 | biostudies-literature
Project description:Pemetrexed (PEM) is a useful drug that can be combined with immune checkpoint blockade therapy for treatment of patients with advanced non-small-cell lung cancer (NSCLC). However, its effects on anti-cancer immunity, especially the sensitivity of NSCLC cells to cytotoxic immune cells, have not been fully investigated. In this study, we examined the effects of PEM on the sensitivity of human NSCLC cells to two different types of cytotoxic immune cells. Pre-treatment with PEM increased the sensitivity of two NSCLC cell lines, PC9 and A549, to activated T cells and natural killer (NK) cells, and decreased the expression of anti-apoptotic proteins, including XIAP and Mcl-1. In addition, PEM treatment increased the cell surface expression of programmed death-ligand 1 (PD-L1) on PC9 cells. PEM-induced upregulation of PD-L1 on PC9 cells was at least partially ascribed to activation of ERK and the NF?B pathway. In contrast, PEM treatment increased the expression of UL16-binding proteins (ULBP), ligands for the NKG2D NK receptor, on PC9 and A549 cells, as well as the induction of senescence. Although the addition of anti-programmed cell death 1 antibody showed no effect on the sensitivity of PEM-treated PC9 and A549 cells to activated T cells, that of anti-NKG2D antibody decreased the enhanced sensitivity of PEM-treated A549 cells to NK cells. These results indicate that PEM can effectively sensitize human NSCLC cells to cytotoxic immune cells while modulating the expression of immune-regulatory molecules.
| S-EPMC7293070 | biostudies-literature
Project description:Radioresistance remains a major clinical challenge in cervical cancer therapy. However, the mechanism for the development of radioresistance in cervical cancer is unclear. Herein, we determined that growth arrest and DNA-damage-inducible protein 45α (GADD45α) is decreased in radioresistant cervical cancer compared to radiosensitive cancer both in vitro and in vivo. In addition, silencing GADD45α prevents cervical cancer cells from undergoing radiation-induced DNA damage, cell cycle arrest, and apoptosis. More importantly, our data show that the overexpression of GADD45α significantly enhances the radiosensitivity of radioresistant cervical cancer cells. These data show that GADD45α decreases the cytoplasmic distribution of APE1, thereby enhancing the radiosensitivity of cervical cancer cells. Furthermore, we show that GADD45α inhibits the production of nitric oxide (NO), a nuclear APE1 export stimulator, by suppressing both endothelial NO synthase (eNOS) and inducible NO synthase (iNOS) in cervical cancer cells. In conclusion, our findings suggest that decreased GADD45α expression significantly contributes to the development of radioresistance and that ectopic expression of GADD45α sensitizes cervical cancer cells to radiotherapy. GADD45α inhibits the NO-regulated cytoplasmic localization of APE1 through inhibiting eNOS and iNOS, thereby enhancing the radiosensitivity of cervical cancer cells.
| S-EPMC5943293 | biostudies-literature
Project description:Deregulated Sonic Hedgehog (SHH) pathway facilitates the initiation, progression, and metastasis of Non-small cell lung cancer (NSCLC), confers drug resistance and renders a therapeutic interference option to lung cancer patients with poor prognosis. In this study, we screened and evaluated the specificity of a Chinese herb Scutellariabarbata D. Don extraction (SBE) in repressing SHH signaling pathway to block NSCLC progression. Our study confirmed that aberrant activation of the SHH signal pathway conferred more proliferative and invasive phenotypes to human lung cancer cells. This study revealed that SBE specifically repressed SHH signaling pathway to interfere the SHH-mediated NSCLC progression and metastasis via arresting cell cycle progression. We also found that SBE significantly sensitized lung cancer cells to chemotherapeutic agent DDP via repressing SHH components in vitro and in vivo. Mechanistic investigations indicated that SBE transcriptionally and specifically downregulated SMO and consequently attenuated the activities of GLI1 and its downstream targets in SHH signaling pathway, which interacted with cell cycle checkpoint enzymes to arrest cell cycle progression and lead to cellular growth inhibition and migration blockade. Collectively, our results suggest SBE as a novel drug candidate for NSCLC which specifically and sensitively targets SHH signaling pathway.
| S-EPMC5432500 | biostudies-literature
Project description:The cellular response to ionizing radiation (IR) depends on tumor cell and microenvironmental factors. Here, we investigated the role of IR-induced ADAM17 matrix metalloproteinase activity for the intercellular communication between tumor cells and the tumor vasculature in non-small cell lung cancer (NSCLC) tumor models. Factors shed by ADAM17 from NSCLC tumor cells (A549, H358) and relevant for endothelial cell migration were investigated using transwell migration assays, ELISA, and flow cytometry. Tumor angiogenesis-related endpoints were analyzed with the chorio-allantoic membrane assay and in murine NSCLC tumor models. Efficacy-oriented experiments were performed in a murine orthotopic NSCLC tumor model using irradiation with an image-guided small-animal radiotherapy platform alone and in combination with the novel ADAM17-directed antibody MEDI3622. In vitro, VEGF was identified as the major factor responsible for IR-induced and ADAM17-dependent endothelial cell migration toward attracting tumor cells. IR strongly enhanced tumor cell-associated ADAM17 activity, released VEGF in an ADAM17-dependent manner, and thereby coordinated the communication between tumor and endothelial cells. In vivo, tumor growth and microvessel size and density were strongly decreased in response to the combined treatment modality of IR and MEDI3622 but not by either treatment modality alone and thus suggest that the supra-additive effect of the combined treatment modality is in part due to abrogation of the ADAM17-mediated IR-induced protective effect on the tumor vasculature. Furthermore, we demonstrate that the novel ADAM17-inhibitory antibody MEDI3622 potently improves the radiotherapy response of NSCLC.SignificanceThe tumor response to radiotherapy is influenced by several factors of the tumor microenvironment. We demonstrate that inhibition of the sheddase ADAM17 by the novel antibody MEDI3622 reduces IR-induced VEGF release from tumor cells relevant for endothelial cell migration and vasculature protection, thereby enhancing radiotherapy treatment outcome of NSCLC.
| S-EPMC9973400 | biostudies-literature
Project description:BackgroundConcurrent thoracic radiation plus chemotherapy is the mainstay of first-line treatment for limited-stage small cell lung cancer (LS-SCLC). Despite initial high responsiveness to combined chemo- and radiotherapy, SCLC almost invariably relapses and develops resistance within one year, leading to poor prognosis in patients with LS-SCLC. Developing new chemical agents that increase ionizing radiation's cytotoxicity against SCLC is urgently needed.ResultsDual histone deacetylase (HDAC) and PI3K inhibitor FK228 not only displayed potent anticancer activity, but also enhanced the therapeutic effects of radiotherapy in SCLC cells. Mechanistically, radioresistant SCLC cells exhibit a lower level of histone H3K9 acetylation and a higher expression level of the MRE11-RAD50-NBS1 (MRN) complex and show more efficient and redundant DNA damage repair capacities than radiosensitive SCLC cells. FK228 pretreatment resulted in marked induction of H3k9 acetylation, attenuated homologous recombination (HR) repair competency and impaired non-homologous end joining (NHEJ) repair efficacy, leading to the accumulation of radiation-induced DNA damage and radiosensitization.ConclusionThe study uncovered that FK228 sensitized human radioresistant SCLC cells to radiation mainly through induction of chromatin decondensation and suppression of DNA damage signaling and repair. Our study provides a rational basis for a further clinical study to test the potential of FK228 as a radiosensitizing agent to increase the radiation-induced tumor cell kill in LS-SCLC patients.
| S-EPMC7905898 | biostudies-literature
Project description:A considerable percentage of rectal cancers are resistant to standard preoperative chemoradiotherapy. Because patients with a priori-resistant tumors do not benefit from multimodal treatment, understanding and overcoming this resistance remains of utmost clinical importance. We recently reported overexpression of the Wnt transcription factor TCF4, also known as TCF7L2, in rectal cancers that were resistant to 5-fluorouracil-based chemoradiotherapy. Because Wnt signaling has not been associated with treatment response, we aimed to investigate whether TCF4 mediates chemoradioresistance. RNA interference-mediated silencing of TCF4 was employed in three colorectal cancer (CRC) cell lines, and sensitivity to (chemo-) radiotherapy was assessed using a standard colony formation assay. Silencing of TCF4 caused a significant sensitization of CRC cells to clinically relevant doses of X-rays. This effect was restricted to tumor cells with high T cell factor (TCF) reporter activity, presumably in a β-catenin-independent manner. Radiosensitization was the consequence of (i) a transcriptional deregulation of Wnt/TCF4 target genes, (ii) a silencing-induced G(2)/M phase arrest, (iii) an impaired ability to adequately halt cell cycle progression after radiation and (iv) a compromised DNA double strand break repair as assessed by γH2AX staining. Taken together, our results indicate a novel mechanism through which the Wnt transcription factor TCF4 mediates chemoradioresistance. Moreover, they suggest that TCF4 is a promising molecular target to sensitize resistant tumor cells to (chemo-) radiotherapy.
| S-EPMC3254167 | biostudies-literature
Project description:Synthetic lethality is an efficient mechanism-based approach to selectively target DNA repair defects. Excision repair cross-complementation group 1 (ERCC1) deficiency is frequently found in non-small-cell lung cancer (NSCLC), making this DNA repair protein an attractive target for exploiting synthetic lethal approaches in the disease. Using unbiased proteomic and metabolic high-throughput profiling on a unique in-house-generated isogenic model of ERCC1 deficiency, we found marked metabolic rewiring of ERCC1-deficient populations, including decreased levels of the metabolite NAD+ and reduced expression of the rate-limiting NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT). We also found reduced NAMPT expression in NSCLC samples with low levels of ERCC1. These metabolic alterations were a primary effect of ERCC1 deficiency, and caused selective exquisite sensitivity to small-molecule NAMPT inhibitors, both in vitro - ERCC1-deficient cells being approximately 1,000 times more sensitive than ERCC1-WT cells - and in vivo. Using transmission electronic microscopy and functional metabolic studies, we found that ERCC1-deficient cells harbor mitochondrial defects. We propose a model where NAD+ acts as a regulator of ERCC1-deficient NSCLC cell fitness. These findings open therapeutic opportunities that exploit a yet-undescribed nuclear-mitochondrial synthetic lethal relationship in NSCLC models, and highlight the potential for targeting DNA repair/metabolic crosstalks for cancer therapy.
| S-EPMC5873862 | biostudies-literature