共查询到20条相似文献,搜索用时 15 毫秒
1.
Ana Milojkovic Philipp G. Hemmati Annika Müer Tim Overkamp Cindrilla Chumduri Reiner U. Jänicke Bernd Gillissen Peter T. Daniel 《International journal of cancer. Journal international du cancer》2013,133(11):2551-2562
The p14ARF tumor suppressor triggers cell death or cell cycle arrest upon oncogenic stress. In MCF‐7 breast carcinoma cells, expression of the tumor suppressor gene p14ARF fails to trigger apoptosis but induces an arrest in the G1 and, to a lesser extent, in the G2 phase in the cell division cycle. Here, inhibition of cell cycle arrest resulted in apoptosis induction in caspase‐3 proficient MCF‐7 cells upon expression of p14ARF. This occurred in the absence of S‐phase progression or mitotic entry. In contrast, syngeneic, caspase‐3‐deficient MCF‐7 cells remained entirely resistant to p14ARF‐induced apoptosis. Thus, cell cycle checkpoint abrogation overcomes resistance to p14ARF‐induced cell death and promotes cell death via a caspase‐3‐dependent pathway. Cell death coincided with dissipation of the mitochondrial membrane potential, release of cytochrome c, and was inhibitable by pan‐caspase inhibitors and the caspase‐3/7 inhibitor zDEVD‐fmk. Of note, mitochondrial events of apoptosis execution depended entirely on caspase‐3 proficiency indicating that caspase‐3 either acts “up‐stream” of the mitochondria in a “non‐canonical” pathway or mediates a mitochondrial feedback loop to amplify the apoptotic caspase signal in p14ARF‐induced stress signaling. 相似文献
2.
Satoru Moriyama Yoshiaki Nakashima Motoki Yano Masahiro Kaji Yosuke Yamakawa Tatsuya Toyama Hiroko Yamashita Hirotaka Iwase Hidefumi Sasaki Yushi Saito Masanobu Kiriyama Jyoji Kato Yoshitaka Fujii 《Cancer science》2002,93(7):783-788
The CDKN2 gene is located on the short arm of chromosome 9p and encodes two unrelated proteins, p16INK4a and p14ARF, through the use of independent first exons and shared exons 2 and 3. p16INK4a is a cyclin‐dependent kinase inhibitor, whereas p14ARF regulates the cell cycle through a p53 and MDM2–dependent pathway. We have examined the expression of p16INK4a and p14ARF using competitive RT‐PCR in 60 non‐small cell lung cancers (NSCLCs) and matching normal lung tissues. The intensities of bands for p16INK4a and p14ARF were nearly equal or the intensity of the p16INK4a band slightly exceeded that of p14ARF in the normal lung tissues (n=60). In 38 tumors the intensity of the p16INK4a band was similar to or slightly weaker than that of p14ARF. In 6 tumors the intensity of the p16INK4a band was weaker than that of p14ARF. In 15 tumors the intensity of the p14ARF band was very strong and the p16INK4a band was barely visible. In only one tumor was the intensity of the p16INK4a band very strong, while the band of p14ARF was barely visible. The ratio of the intensity of p16INK4a to p14ARF had an interesting correlation with the tumor's clinicopathological characteristics. The p stage II‐IV tumors had significantly lower p16INK4a to p14ARF ratios than the p stage I tumors (P=0.036). The T2–4 tumors had significantly lower p16INK4a to p14ARF ratios than the T1 tumors (P=0.005). The N1–3 tumors had significantly lower p16INK4a to p14ARF ratios than the NO tumors (P=0.014). Our results suggest that the ratio of expression of p16INK4a to p14ARFtends to decrease during the progression of NSCLC. 相似文献
3.
SB Vestey C Sen CJ Calder CM Perks M Pignatelli ZE Winters 《Breast cancer research : BCR》2004,6(5):R571
Introduction
p14ARF stabilises nuclear p53, with a variable expression of p14ARF mRNA in breast cancers. In vitro, nuclear p14ARF binds Hdm2 to block Hdm2-dependent nucleocytoplasmic shuttling of p53, which is required before cytoplasmic degradation of p53. p14ARF is negatively regulated by p53 and through p53-independent pathways. No studies have yet examined levels of p14ARF protein expression in breast cancer and their relationship to Hdm2/p53 immunoreactivity or subcellular localisation. Previously, immunohistochemical expression of cytoplasmic p14ARF, p53 and Hdm2 has been described. HER-2 (c-erbB2/neu) predicts prognosis and interacts with the p14ARF/Hdm2 pathway to inactivate p14ARF and to influence Hdm2 activity and localisation. This study examined p14ARF and p53/Hdm2 expression and subcellular localisation by using immunohistochemistry in a series of invasive ductal breast cancers (IDCs) with concomitant ductal carcinoma in situ (DCIS), to evaluate whether findings in vitro were related to clinicopathological parameters such as HER-2 and their effect on patient outcome. 相似文献4.
Alexander Damalas Georgia Velimezi Alexander Kalaitzakis Michalis Liontos Athanasios G. Papavassiliou Vassilis Gorgoulis Charalampos Angelidis 《International journal of cancer. Journal international du cancer》2011,128(8):1989-1995
The p14ARF is a key tumor suppressor induced mainly by oncogenic stimuli. Although p14ARF does not seem to respond to DNA damage, there are very few data regarding its role in other forms of stress, such as heat shock (HS) and oxidative stress (OS). Here, we report that suppression of p14ARF increased resistance to cell death when cells were treated with H2O2 or subjected to HS. In this setting, protection from cell death was mediated by elevated levels and activity of β‐catenin, as downregulation of β‐catenin alleviated the protective role of p14ARF silencing. Moreover, Hsp70 was shown to regulate β‐catenin protein levels by interacting with p14ARF, suggesting that Hsp70, p14ARF and β‐catenin form a regulatory network. This novel pathway triggers cell death signals when cells are exposed to HS and OS. 相似文献
5.
BACKGROUND:
p14ARF, an alternate reading frame (ARF) product of the cyclin‐dependent kinase inhibitor 2A locus, plays a critical role in crosstalk between the tumor protein 53 (p53) and retinoblastoma (Rb) pathways and in cellular anticancer mechanisms. Therefore, the authors of this report investigated the association between single nucleotide polymorphisms (SNPs) of the p14ARF gene and the risk of developing a second primary malignancy (SPM) after an index squamous cell carcinoma of the head and neck (SCCHN).METHODS:
The log‐rank test and Cox proportional hazards models were used to assess the association of 2 p14ARF SNPs (reference SNP [rs]3731217 and rs3088440) with SPM‐free survival and with the risk of developing an SPM among 1287 patients who had SCCHN.RESULTS:
Patients with either p14ARF variant genotypes of the 2 polymorphisms had a significantly reduced SPM‐free survival compared with patients with no variant genotypes (log‐rank test; P = .006). Compared with the p14ARF thymine‐thymine (TT) and guanine‐guanine (GG) genotypes, the variant genotypes of p14ARF TG/GG and guanine‐adenine (GA)/AA were associated with a significantly moderately increased risk of developing an SPM (p14ARF rs3731217: adjusted hazard ratio [aHR], 1.48; 95% confidence interval [CI], 1.00‐2.19; p14ARF rs3088440: aHR, 1.61; 95% CI, 1.07‐2.43). Moreover, after combining the variant genotypes of the 2 SNPs, patients who had variant genotypes were at significantly greater risk of developing an SPM compared with patients who had no variant genotypes (aHR, 3.07; 95% CI, 1.54‐6.12), and the risk was particularly pronounced in several subgroups.CONCLUSIONS:
The current results suggested that there is a modestly increased risk of developing an SPM after an index SCCHN with each p14ARF polymorphism, and there is an even greater risk of developing an SPM for patients with combined variant genotypes of the 2 SNPs. Therefore, p14ARF polymorphisms may be susceptible markers of the risk of developing an SPM in patients with SCCHN. Cancer 2011. © 2010 American Cancer Society. 相似文献6.
Jessica Thevenard Laurent Ramont Jrome Devy Bertrand Brassart Aurlie Dupont‐Deshorgue Nicolas Floquet Laurence Schneider Farid Ouchani Christine Terryn Franois‐Xavier Maquart Jean‐Claude Monboisse Sylvie Brassart‐Pasco 《International journal of cancer. Journal international du cancer》2010,126(5):1055-1066
We previously demonstrated that the CNYYSNS peptide derived from tumstatin inhibited in vivo tumor progression. The YSNS motif formed a β‐turn crucial for biological activity. More recently, a YSNSG cyclopeptide with a constrained β‐turn on the YSNS residues was designed. Intraperitoneal administration of the YSNSG cyclopeptide inhibited in vivo melanoma progression more efficiently than the native linear peptide. In the present article, we showed that the YSNSG cyclopeptide also triggered an inhibition of in vivo tumor neovascularization and we further analyzed its in vitroantiangiogenic effect. The YSNSG cyclopeptide did not alter endothelial cell proliferation but inhibited cell migration by 83% in an in vitro wound healing model. The inhibition was mediated by a decrease in active MT1‐MMP at the migration front as well as a decrease in u‐PA and u‐PAR expression. The cyclopeptide also altered β1‐integrin distribution in endothelial cell lamellipodia, induced a strong decrease in the phosphorylated focal adhesion kinase (p125FAK), disorganized F‐actin stress fibers and decreased the number of lamellipodia, resulting in a non migratory phenotype. Our results confirm the YSNSG cyclopeptide as a potent antitumor agent, through both the inhibition of invasive properties of tumor cells and the antiangiogenic activity. 相似文献
7.
Panobinostat sensitizes KRAS‐mutant non‐small‐cell lung cancer to gefitinib by targeting TAZ
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Wen‐Ying Lee Pin‐Cyuan Chen Wen‐Shin Wu Han‐Chung Wu Chun‐Hsin Lan Yen‐Hua Huang Chia‐Hsiung Cheng Ku‐Chung Chen Cheng‐Wei Lin 《International journal of cancer. Journal international du cancer》2017,141(9):1921-1931
8.
Krüppel‐like factor 4 promotes c‐Met amplification‐mediated gefitinib resistance in non‐small‐cell lung cancer
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Wei Feng Qianyi Xie Suo Liu Ying Ji Chunyun Li Chunle Wang Longyu Jin 《Cancer science》2018,109(6):1775-1786
Gefitinib has been widely used in the first‐line treatment of advanced EGFR‐mutated non‐small‐cell lung cancer (NSCLC). However, many NSCLC patients will acquire resistance to gefitinib after 9‐14 months of treatment. This study revealed that Krüppel‐like factor 4 (KLF4) contributes to the formation of gefitinib resistance in c‐Met‐overexpressing NSCLC cells. We observed that KLF4 was overexpressed in c‐Met‐overexpressing NSCLC cells and tissues. Knockdown of KLF4 increased tumorigenic properties in gefitinib‐resistant NSCLC cell lines without c‐Met overexpression, but it reduced tumorigenic properties and increased gefitinib sensitivity in gefitinib‐resistant NSCLC cells with c‐Met overexpression, whereas overexpression of KLF4 reduced gefitinib sensitivity in gefitinib‐sensitive NSCLC cells. Furthermore, Western blot analysis revealed that KLF4 contributed to the formation of gefitinib resistance in c‐Met‐overexpressing NSCLC cells by inhibiting the expression of apoptosis‐related proteins under gefitinib treatment and activating the c‐Met/Akt signaling pathway by decreasing the inhibition of β‐catenin on phosphorylation of c‐Met to prevent blockade by gefitinib. In summary, this study's results suggest that KLF4 is a promising candidate molecular target for both prevention and therapy of NSCLC with c‐Met overexpression. 相似文献
9.
Human astrocytomas are characterized by a number of molecular changes affecting two critical tumor suppressor pathways: the
pRB and the p53 pathways. Genetic alterations functionally eliminate pRB and p53 themselves or upstream and/or downstream
molecules such as products of theInk4a/ARF locus, p16Ink4a and p14ARF. As a result, malignant cells are defective in critical cell cycle and apoptosis regulatory elements contributing to unrelenting
tumour growth and invasion. Current research aims to discover effective means of reconstituting p53 and pRB pathway components
in an effort to attenuate the aggressive phenotype of astrocytoma. 相似文献
10.
11.
Kunihiko Minakata Fumiyuki Takahashi Takeshi Nara Muneaki Hashimoto Ken Tajima Akiko Murakami Fariz Nurwidya Suzu Yae Fumiaki Koizumi Hiroyuki Moriyama Kuniaki Seyama Kazuto Nishio Kazuhisa Takahashi 《Cancer science》2012,103(11):1946-1954
Somatic mutations in the epidermal growth factor receptor (EGFR) gene, such as exon 19 deletion mutations, are important factors in determining therapeutic responses to gefitinib in non‐small‐cell lung cancer (NSCLC). However, some patients have activating mutations in EGFR and show poor responses to gefitinib. In this study, we examined three NSCLC cell lines, HCC827, PC9, and HCC2935, that expressed an EGFR exon 19 deletion mutation. All cells expressed mutant EGFR, but the PC9 and HCC2935 cells also expressed wild‐type EGFR. The HCC827 cells were highly sensitive to gefitinib under both normoxia and hypoxia. However, the PC9 and HCC2935 cells were more resistant to gefitinib under hypoxic conditions compared to normoxia. Phosphorylation of EGFR and ERK was suppressed with gefitinib treatment to a lesser extent under hypoxia. The expression of transforming growth factor‐α (TGFα) was dramatically upregulated under hypoxia, and the knockdown of TGFα or hypoxia‐inducible factor‐1α (HIF1α) reversed the resistance to gefitinib in hypoxic PC9 and HCC2935 cells. Finally, introduction of the wild‐type EGFR gene into the HCC827 cells caused resistance to gefitinib under hypoxia. This phenomenon was also reversed by the knockdown of TGFα or HIF1α. Our results indicate that hypoxia causes gefitinib resistance in EGFR‐mutant NSCLC through the activation of wild‐type EGFR mediated by the upregulation of TGFα. The presence of wild‐type and mutant EGFR along with tumor hypoxia are important factors that should be considered when treating NSCLC patients with gefitinib. 相似文献
12.
Chandramu Chetty Praveen Bhoopathi Jasti S. Rao Sajani S. Lakka 《International journal of cancer. Journal international du cancer》2009,124(10):2468-2477
Matrix metalloproteinase‐2 (MMP‐2), is known to degrade the collagen IV, plays a role in radiation‐induced lung injury. We therefore investigated the antitumor effects of combining MMP‐2 inhibition using an adenovirus expressing siRNA against MMP‐2 (Ad‐MMP‐2‐Si) with radiation therapy (IR) on A549 lung cancer cells in vitro and in vivo. IR increased MMP‐2 mRNA, protein and activity in lung cancer cells. MMP‐2 inhibition along with IR enhanced radiosensitivity as determined by clonogenic assay, flow cytometry and TUNEL assay. We show that MMP‐2 inhibition prior to irradiation reduced p53 phosphorylation, with a corresponding reduction in the expression of the p53 downstream target gene p21Cip1/Waf1. Irradiated tumor cells induced the FoxM1‐mediated DNA repair gene, XRCC1 and Checkpoint kinases 2/1, which were abrogated with combined treatment of Ad‐MMP‐2‐Si and IR. Further, the combination of Ad‐MMP‐2‐Si with radiotherapy significantly increased antitumor efficacy in vivo compared to either agent alone. Indeed, histological analysis of tumor sections collected from the combination group revealed more apoptotic cells. These studies suggest that MMP‐2 inhibition in combination with radiotherapy abrogates G2 cell cycle arrest leading to apoptosis and provide evidence of the antitumor efficacy of combining MMP‐2 inhibition with irradiation as a new therapeutic strategy for the effective treatment of NSCLC patients. © 2008 Wiley‐Liss, Inc. 相似文献
13.
Inhibition of experimental small‐cell and non‐small‐cell lung cancers by novel antagonists of growth hormone‐releasing hormone
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Haibo Wang Xianyang Zhang Irving Vidaurre Renzhi Cai Wei Sha Andrew V. Schally 《International journal of cancer. Journal international du cancer》2018,142(11):2394-2404
14.
15.
In vivo antitumor function of tumor antigen‐specific CTLs generated in the presence of OX40 co‐stimulation in vitro
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Ngoc Pham Minh Satoshi Murata Naomi Kitamura Tomoyuki Ueki Masatsugu Kojima Toru Miyake Katsushi Takebayashi Hirokazu Kodama Eiji Mekata Masaji Tani 《International journal of cancer. Journal international du cancer》2018,142(11):2335-2343
Adoptive cell transfer (ACT) is an emerging and promising cancer immunotherapy that has been improved through various approaches. Here, we described the distinctive characteristics and functions of tumor Ag‐specific effector CD8+ T‐cells, co‐cultured with a tumor‐specific peptide and a stimulatory anti‐OX40 antibody, before being used for ACT therapy in tumor‐bearing mouse recipients. Splenic T‐cells were obtained from wild‐type FVB/N mice that had been injected with a HER2/neu (neu)‐expressing tumor and a neu‐vaccine. The cells were then incubated for 7 days in vitro with a major histocompatibility complex (MHC) class I peptide derived from neu, in the presence or absence of an agonistic anti‐OX40 monoclonal antibody, before CD8+ T cells were isolated for use in ACT therapy. The proliferative ability of OX40‐driven tumor Ag‐specific effector CD8+ T‐cells in vitro was less than that of non‐OX40‐driven tumor Ag‐specific effector CD8+ T‐cells, but they expressed significantly more early T‐cell differentiation markers, such as CD27, CD62L and CCR7, and significantly higher levels of Bcl‐2, an anti‐apoptotic protein. These OX40‐driven tumor Ag‐specific effector CD8+ T‐cells, when transferred into tumor‐bearing recipients, demonstrated potent proliferation capability and successfully eradicated the established tumor. In addition, these cells exhibited long‐term antitumor function, and appeared to be established as memory T‐cells. Our findings suggest a possible in vitro approach for improving the efficacy of ACT, which is simple, requires only a small amount of modulator, and can potentially avoid several toxicities associated with co‐stimulation in vivo. 相似文献
16.
Michael O'Hare Mehdi Shadmand Rania S. Sulaiman Kamakshi Sishtla Toshiaki Sakisaka Timothy W. Corson 《International journal of cancer. Journal international du cancer》2016,139(8):1752-1758
The mitotic kinesin KIF14 has an essential role in the recruitment of proteins required for the final stages of cytokinesis. Genomic gain and/or overexpression of KIF14 has been documented in retinoblastoma and a number of other cancers, such as breast, lung and ovarian carcinomas, strongly suggesting its role as an oncogene. Despite evidence of oncogenic properties in vitro and in xenografts, Kif14's role in tumor progression has not previously been studied in a transgenic cancer model. Using a novel Kif14 overexpressing, simian virus 40 large T‐antigen retinoblastoma (TAg‐RB) double transgenic mouse model, we aimed to determine Kif14's role in promoting retinal tumor formation. Tumor initiation and development in double transgenics and control TAg‐RB littermates were documented in vivo over a time course by optical coherence tomography, with subsequent ex vivo quantification of tumor burden. Kif14 overexpression led to an accelerated initiation of tumor formation in the TAg‐RB model and a significantly decreased tumor doubling time (1.8 vs. 2.9 weeks). Moreover, overall percentage tumor burden was also increased by Kif14 overexpression. These data provide the first evidence that Kif14 can promote tumor formation in susceptible cells in vivo. 相似文献
17.
Jie He Jian-bing Qiao Haiqing Zhu 《Medical oncology (Northwood, London, England)》2011,28(4):1218-1224
Methylation in the promoter region is one of the mechanisms through which tumor suppressors are inactivated, resulting in
tumorigenesis and/or tumor progression. Herein, we studied the methylation status in the promoter region of the p14ARF tumor suppressor gene in 33 brain tissues isolated from glioma patients (astrocytomas) and compared to 12 brain tissues isolated
from autopsy donors using methylation-specific polymerase chain reaction (MSP). The correlation between the expression of
P14 and P53 was investigated using immunohistochemistry (IHC). The average percentage of methylation in the promoter region
of p14ARF gene in brain samples from glioma patients is 39.4%, while 0 from autopsy donors. No difference in the methylation level
between low-grade and high-grade gliomas was detected. The methylation status has no correlation with the prognosis in glioma
patients. A significant correlation between the expression of mutant form of TP53 and the grade of the glioma was established.
Furthermore, there was a negative correlation between methylation of the p14ARF promoter and the expression of the mutant form of TP53. Therefore, our data suggest that methylation in the promoter region
of the p14ARF gene may be used as a biomarker for the diagnosis of gliomas. 相似文献
18.
Manabu Kawada Hiroyuki Inoue Shun‐Ichi Ohba Tohru Masuda Isao Momose Daishiro Ikeda 《International journal of cancer. Journal international du cancer》2010,126(4):810-818
Targeting stroma in tumor tissues is an attractive new strategy for cancer treatment. We developed in vitro coculture system, in which the growth of human prostate cancer DU‐145 cells is stimulated by prostate stromal cells (PrSC) through insulin‐like growth factor I (IGF‐I). Using this system, we have been searching for small molecules that inhibit tumor growth through modulation of tumor‐stromal cell interactions. As a result, we have found that leucinostatins and atpenins, natural antifungal antibiotics, inhibit the growth of DU‐145 cells cocultured with PrSC more strongly than that of DU‐145 cells alone. In this study we examined the antitumor effects of these small molecules in vitro and in vivo. When DU‐145 cells were coinoculated with PrSC subcutaneously in nude mice, leucinostatin A was found to significantly suppress the tumor growth more than atpenin B. The antitumor effect of leucinostatin A in vivo was not obtained against the tumors of DU‐145 cells alone. RT‐PCR experiments revealed that leucinostatin A specifically inhibited IGF‐I expression in PrSC without effect on expressions of other IGF axis molecules. Leucinostatins and atpenins are known to abrogate mitochondrial functions. However, when we used mitochondrial DNA‐depleted, pseudo‐ρ0 cells, we found that one of leucinostain A actions certainly depended on mitochondrial function, but it actually inhibited the growth of DU‐145 cells more strongly in coculture with pseudo‐ρ0 PrSC and reduced IGF‐I expression in pseudo‐ρ0 PrSC. Taken together, our results suggested that leucinostatin A inhibited prostate cancer cell growth through reduction of IGF‐I expression in PrSC. 相似文献
19.
20.
MiR‐503 targets PI3K p85 and IKK‐β and suppresses progression of non‐small cell lung cancer
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Yi Yang Lei Liu Ying Zhang Hongyu Guan Jueheng Wu Xun Zhu Jie Yuan Mengfeng Li 《International journal of cancer. Journal international du cancer》2014,135(7):1531-1542
A microRNA usually has the ability to coordinately repress multiple target genes and therefore are associated with many pathological conditions such as human cancer. Our understanding of the biological roles of microRNAs in lung cancer, however, remains incomplete. In this study, we identified miR‐503 as a tumor‐suppressive microRNA in human non‐small cell lung carcinoma (NSCLC), whose expression level correlates inversely with overall survival in NSCLC patients. Ectopic expression of miR‐503 suppressed tumor cell proliferation and metastasis‐related traits in vitro as well as in vivo, supporting a anti‐cancer role of the microRNA in NSCLC progression. Mechanistic study revealed that oncogenic PI3K p85 and IKK‐β were direct targets of miR‐503. Overexpression of either PI3K p85 or IKK‐β partially restored the malignant properties of NSCLC cells in the presence of miR‐503. Taken together, our data demonstrate miR‐503 inhibits the malignant phenotype of NSCLC by targeting PI3K p85 and IKK‐β and might play a suppressive role in the pathogenesis of NSCLC, thus providing new insights in developing novel diagnostic and therapeutic approaches. 相似文献