Identification of a 170-kDa protein over-expressed in lung cancers

Pincheira, Roxana; Chen, Q.; Zhang, Jianting

doi:10.1054/bjoc.2001.1828

Cited by 96 publications

(85 citation statements)

References 40 publications

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“…Western blot analysis was performed as described previously (Zhang et al, 1993;Pincheira et al, 2001;Yang et al, 2002). In brief, cell lysates or plasma membranes were solubilized in SDS sample buffer and separated by SDS-polyacrylamide gel electrophoresis followed by transfer to a PVDF membrane.…”

Section: Methodsmentioning

confidence: 99%

Expression Profiling of ABC Transporters in a Drug-Resistant Breast Cancer Cell Line Using AmpArray

Yang

Peng

Zhang³

2005

Mol Pharmacol

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ATP-binding cassette (ABC) membrane proteins comprise a superfamily of transporters with a wide variety of substrates. Humans have 49 members in this superfamily. Several human ABC transporters, such as ABCB1 and ABCC1, have been attributed to cause multidrug resistance (MDR) in cancer treatment when over-expressed. In the past, an MDR cancer cell line MCF7/AdVp3000 has been selected, and overexpression of ABCG2 was thought to cause MDR in this cell line. However, ectopic overexpression of ABCG2 in MCF7 cells could not explain the high drug resistance level observed with the selected cell line. In this study, we designed an AmpArray analysis to profile whether other ABC transporters were also selected to contribute to the increased drug resistance in MCF7/AdVp3000 cells. We found that 16 ABC transporters, including ABCG2, had Ն1.5-fold altered expression in MCF7/AdVp3000 compared with the parental MCF7 cells. In particular, the expression of ABCA4 and ABCC3 was increased by 132-and 459-fold, respectively, whereas ABCG2 was increased by ϳ3000-fold. Furthermore, the elevated expression of these three transporters reversed with the reversed drug resistance phenotype, and silencing ABCC3 expression in MCF7/ AdVp3000 cells significantly reduced doxorubicin resistance. Thus, other ABC transporters in addition to ABCG2 are likely to contribute to the MDR selected in MCF7/AdVp3000 cells. This study also shows that AmpArray can be used as a quick and easy tool to profile the expression of ABC transporters in resistant cell lines and tumor samples for potential use in individualized design of therapy.Drug resistance to chemotherapy frequently occurs in cancers and is a major obstacle to successful cancer treatment. Studies with tumor cell lines have revealed that multidrug resistance (MDR) can develop and thus cause chemotherapy failure. Advances in elucidating the molecular basis of the MDR phenotype indicate that elevated membrane expression of several drug efflux pumps such as P-glycoprotein (Pgp or ABCB1), multidrug resistance protein 1 (MRP1 or ABCC1), and ABCG2 is a frequent cause of MDR in human cancers

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Section: Methodsmentioning

confidence: 99%

Expression Profiling of ABC Transporters in a Drug-Resistant Breast Cancer Cell Line Using AmpArray

Yang

Peng

Zhang³

2005

Mol Pharmacol

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“…eIF3a (p150, also known as p170) is the largest eIF3 subunit and is overexpressed in a variety of tumours when compared with normal control tissues. These include cancers of the breast, cervix, esophagus and lung (Lin et al, 2001;Pincheira et al, 2001). eIF3b (p116) has also been found significantly up- (Lin et al, 2001).…”

Section: Eif3mentioning

confidence: 99%

Translation initiation and its deregulation during tumorigenesis

Watkins

Norbury

2002

Br J Cancer

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Regulation of protein synthesis at the level of translation initiation is fundamentally important for the control of cell proliferation under normal physiological conditions. Conversely, misregulation of protein synthesis is emerging as a major contributory factor in cancer development. Most bulk protein synthesis is initiated via recognition of the mRNA 5' cap and subsequent recognition of the initiator AUG codon by a directional scanning mechanism. However, several key regulators of tumour development are translated by a cap-independent pathway. Here we review eukaryotic translation initiation, its regulation and the ways in which this regulation can break down during tumorigenesis. TRANSLATION RATES AND GROWTH CONTROLCell growth and proliferation rates depend critically upon the rate of protein synthesis. Normal cells that are able to proliferate generally do so transiently in response to appropriate extracellular cues. Withdrawal of these growth stimuli leads to cell cycle exit associated with a marked decrease in protein synthesis. In mammalian fibroblasts, inhibiting overall protein translation by 50% is sufficient to prevent the onset of DNA replication following mitogenic stimulation. Consequently there exists a critical threshold level of total protein synthesis, which must be exceeded in order to commit each cell to a round of replication. This has been interpreted as a requirement to accumulate one or more unstable protein(s) to a predetermined level. The G1 cyclins have emerged as prime candidates for this class of regulatory proteins (reviewed in Zetterberg et al, 1995).The rate of synthesis of any given protein is determined primarily by the level of translation initiation. In mammalian cells, this is a complex process that requires collaboration between multiple eukaryotic initiation factors (eIFs: reviewed in Pestova et al, 2001). In brief, a ternary complex is formed between eIF2, GTP and the initiator methionyl-tRNA (met-tRNAi), while free 40S ribosomal subunits are bound to eIF3, a large, multi-subunit, initiation factor. Free 60S ribosomal units are similarly bound to the monomeric eIF6. Together, eIF3 and eIF6 prevent premature association of the 60S and 40S ribosomal subunits. The ternary complex is transferred to eIF3/40S along with eIF1 and eIF1A, to form a 43S pre-initiation complex. eIF3 can now bind to the eIF4F complex, which is associated with the mRNA, thus linking the 40S ribosome to the mRNA and generating the 48S pre-initiation complex (Figure 1). eIF4F itself consists of three components: eIF4G, eIF4E, and eIF4A. eIF4G binds eIF3 and acts as a scaffold for eIF4E and eIF4A. eIF4E recognises and binds the 5' mRNA cap structure while the RNAdependent ATPase eIF4A is thought to unwind secondary structure in the 5' untranslated region (UTR). eIF4B is an additional factor that may stimulate the eIF4A helicase activity and promote RNA binding. The poly(A) tail of the mRNA interacts with poly(A) binding protein (PABP), which in turn has a binding site on eIF4G allowing the mRNA to circ...

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“…eIF3a, the largest subunit of eIF3 complex, has been shown to play a role in regulating synthesis of proteins including a-tubulin, ribonucleotide reductase M2, and p27 (19,20) as well as in cell proliferation (19), cell cycle control (21), and cell differentiation (22). Overexpression of eIF3a has been found in many cancers such as cancers of lung (23), breast (23), cervix (24), stomach (25), and esophagus (26). eIF3a appeared to be essential for cancer cells to maintain malignant phenotype (19) and ectopic overexpression of eIF3a transformed NIH3T3 cells in vitro (27).…”

Section: Introductionmentioning

confidence: 99%

Effect of eIF3a on Response of Lung Cancer Patients to Platinum-Based Chemotherapy by Regulating DNA Repair

Yin

Shen

Dong

et al. 2011

Clinical Cancer Research

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Purpose: The purpose of this study is to test the hypothesis that eIF3a may regulate the expression of DNA repair proteins which, in turn, affects response of lung cancer patients to treatments by DNAdamaging anticancer drugs.Experimental Design: Immunohistochemistry was used to determine the expression of eIF3a in 211 human lung cancer tissues followed by association analysis of eIF3a expression with patient's response to platinum-based chemotherapy. Ectopic overexpression and RNA interference knockdown of eIF3a were carried out in NIH3T3 and H1299 cell lines, respectively, to determine the effect of altered eIF3a expression on cellular response to cisplatin, doxorubicine, etoposide (VP-16), vincristine, and vinblastine by using MTT assay. The DNA repair capacity of these cells was evaluated by using host-cell reactivation assay. Real-time reverse transcriptase PCR and Western Blot analyses were carried out to determine the effect of eIF3a on the DNA repair genes by using cells with altered eIF3a expression.Results: eIF3a expression associates with response of lung cancer patients to platinum-based chemotherapy. eIF3a knockdown or overexpression, respectively, increased and decreased the cellular resistance to cisplatin and anthrocycline anticancer drugs, DNA repair activity, and expression of DNA repair proteins.Conclusions: eIF3a plays an important role in regulating the expression of DNA repair proteins which, in turn, contributes to cellular response to DNA-damaging anticancer drugs and patients' response to platinum-based chemotherapy. Clin Cancer Res; 17(13); 4 -9. Ó2011 AACR.

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Identification of a 170-kDa protein over-expressed in lung cancers

Cited by 96 publications

References 40 publications

Expression Profiling of ABC Transporters in a Drug-Resistant Breast Cancer Cell Line Using AmpArray

Expression Profiling of ABC Transporters in a Drug-Resistant Breast Cancer Cell Line Using AmpArray

Translation initiation and its deregulation during tumorigenesis

Effect of eIF3a on Response of Lung Cancer Patients to Platinum-Based Chemotherapy by Regulating DNA Repair

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