Increased levels and defective glycosylation of MRPs in ovarian carcinoma cells resistant to oxaliplatin

Beretta, Giovanni Luca; Benedetti, Valentina; Cossa, Giacomo; Assaraf, Yehuda G.; Bram, Eran; Gatti, Laura; Corna, Elisabetta; Carenini, Nives; Colangelo, Donato; Howell, Stephen B.; Zunino, Franco; Perego, Paola

doi:10.1016/j.bcp.2009.12.002

Cited by 97 publications

(75 citation statements)

References 37 publications

(47 reference statements)

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“…In general, these findings can be attributed to the fact that the translational processing from mRNA into a functional protein is a complex process involving multiple steps that determine protein functionality. [55][56][57] The observed mRNA expression of FRα is in good agreement with reports revealing elevated FR levels (approximately 50%) in breast tumors and nonelevated (or even slightly reduced) levels in bladder tumors. 28,58,59 Opposed to this, the protein level of FRα showed a cell line-specific glycosylation state that was almost in line with the observed cytotoxicity of MTX-MNP.…”

Section: International Journal Of Nanomedicine Downloaded From Httpssupporting

confidence: 87%

Heterogeneous response of different tumor cell lines to methotrexate-coupled nanoparticles in presence of hyperthermia

Stapf¹,

Pömpner²,

Teichgräber³

et al. 2016

IJN

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Today, the therapeutic efficacy of cancer is restricted by the heterogeneity of the response of tumor cells to chemotherapeutic drugs. Since those therapies are also associated with severe side effects in nontarget organs, the application of drugs in combination with nanocarriers for targeted therapy has been suggested. Here, we sought to assess whether the coupling of methotrexate (MTX) to magnetic nanoparticles (MNP) could serve as a valuable tool to circumvent the heterogeneity of tumor cell response to MTX by the combined treatment with hyperthermia. To this end, we investigated five breast cancer cell lines of different origin and with different mutational statuses, as well as a bladder cancer cell line in terms of their response to exposure to MTX as a free drug or after its coupling to MNP as well as in presence/absence of hyperthermia. We also assessed whether the effects could be connected to the cell line-specific expression of proteins related to the uptake and efflux of MTX and MNP. Our results revealed a very heterogeneous and cell line-dependent response to an exposure with MTX-coupled MNP (MTX–MNP), which was almost comparable to the efficacy of free MTX in the same cell line. Moreover, a cell line-specific and preferential uptake of MTX–MNP compared with MNP alone was found (probably by receptor-mediated endocytosis), agreeing with the observed cytotoxic effects. Opposed to this, the expression pattern of several cell membrane transport proteins noted for MTX uptake and efflux was only by tendency in agreement with the cellular toxicity of MTX–MNP in different cell lines. Higher cytotoxic effects were achieved by exposing cells to a combination of MTX–MNP and hyperthermal treatment, compared with MTX or thermo-therapy alone. However, the heterogeneity in the response of the tumor cell lines to MTX could not be completely abolished – even after its combination with MNP and/or hyperthermia – and the application of higher thermal dosages might be necessary.

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Section: International Journal Of Nanomedicine Downloaded From Httpssupporting

confidence: 87%

Heterogeneous response of different tumor cell lines to methotrexate-coupled nanoparticles in presence of hyperthermia

Stapf¹,

Pömpner²,

Teichgräber³

et al. 2016

IJN

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“…41 In addition, it has been demonstrated that defective multidrug resistance proteins lead to platinum resistance. 42 Defects in N-glycosylation also may affect tumor growth in cells with deregulated phosphatidylinositol 3-kinase/v-Akt murine thymoma viral oncogene homolog (PI3K-Akt) pathway. 26 We have observed that reconstitution of TUSC3 in vitro decreases proliferation as well as binding of cancer cells to the extracellular matrix.…”

Section: Discussionmentioning

confidence: 99%

Methylation status of TUSC3 is a prognostic factor in ovarian cancer

Pils

Horak

Vaňhara

et al. 2012

Cancer

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BACKGROUND. Current prognostic information in ovarian cancer is based on tumor stage, tumor grade, and postoperative tumor size. Reliable molecular prognostic markers are scarce. In this article, the authors describe epigenetic events in a frequently deleted region on chromosome 8p22 that influence the expression of tumor suppressor candidate 3 (TUSC3), a putative tumor suppressor gene in ovarian cancer. METHODS. Messenger RNA expression and promoter hypermethylation of TUSC3 were studied in ovarian cancer cell lines and in tumor samples from 2 large, independent ovarian cancer cohorts using polymerase chain reaction-based methods. RESULTS. The results indicated that TUSC3 expression is decreased significantly because of promoter methylation in malignant ovarian tumors compared with benign controls. Almost 33% of ovarian cancer samples had detectable TUSC3 promoter methylation. Furthermore, methylation status of the TUSC3 promoter had a significant and independent influence on progression-free and overall survival. CONCLUSIONS. TUSC3 hypermethylation predicted progression-free and overall survival in ovarian cancer. The current observations suggested a role for N-glycosylating events in ovarian cancer pathogenesis in general and identified the epigenetic silencing of TUSC3 as a prognostic factor in this disease. Cancer 2013;119:946-54. V C 2012 American Cancer Society.KEYWORDS: TUSC3, methylation, ovarian cancer, glycosylation, progression-free survival, overall survival, biomarker.. INTRODUCTIONEpithelial ovarian cancer is the most lethal gynecologic malignancy and the fourth most frequent cause of cancer-related death among women in industrialized countries. 1 Because >75% of women are diagnosed with advanced disease (International Federation of Gynecology and Obstetrics [FIGO] stages III and IV), an early diagnosis presents 1 of the challenges of this disease. Patients with advanced ovarian cancer undergo intensive multimodal therapy consisting of cytoreductive surgery and (neo)adjuvant platinum-based and taxane-based chemotherapy. Regardless of the progress made in surgical and medical therapies over recent decades, the outcome for women with advanced ovarian cancer remains grim. Innovative, hypothesis-driven approaches to biomarker development remain essential even in the era of high-throughput sequencing and various omics. Studies of promoter methylation patterns in tumor suppressor genes have yielded several promising methylated biomarker candidates. [2][3][4] In contrast to a gene or protein expression analysis, methylation can easily be detected using polymerase chain reaction (PCR)-based methods in both tumor material and body fluids. [5][6][7] TUSC3 (tumor suppressor candidate 3), originally named N33, was identified as a potential tumor suppressor gene in prostate cancer 8,9 and is located on chromosome band 8p22. Known homozygous deletions of this region in pancreatic cell lines 10,11 and prostate cancer cell lines 12,13 contain no other cancer-related genes except TUSC3, although mutations of the T...

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“…Zhang et al showed that n-glycomic alterations were associated with adriamycin resistance in human leukemia (9). increased levels and defective n-glycosylation of multidrug resistance-associated proteins (MrPs) in ovarian carcinoma cells resistant to oxaliplatin have also been reported (10). in addition, n-glycans bearing a β-1-6-linked glcnac branch are consistently elevated in concert with increased expression of Mgat5, and direct correlation has been made between Mgat5 overexpression and enhanced drug resistance (11).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of β3GnT8 reverses 5-fluorouracil resistance in human colorectal cancer cells via inhibition the biosynthesis of polylactosamine-type N-glycans

Shen

et al. 2014

International Journal of Oncology

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Abstract. aber rant glycosylation is known to be associated with cancer chemoresistance. β-1,3-n-acetylglucosaminyltransferase (β3gnt)8, which synthesizes polylactosamine on β1-6 branched n-glycans, is dramatically upregulated in colorectal cancer (crc). 5-fluorouracil (5-fu) resistance remains a major obstacle to the chemotherapy of crc. However, little is known with regard to the correlation between 5-fu resistance and the expression of β3gnt8 in crc. in this study, a 5-fu-resistant cell line (SW620/5-fu) was generated, and 50% inhibition concentration (ic50) of 5-fu was determined by Mtt assay. flow cytometry and lectin blot analysis were performed to detect the alteration of polylactosamine structures. Quantitative rt-Pcr and western blot analysis were used to identify and evaluate candidate genes involved in the synthesis of polylactosamine in SW620/5-fu cells. We found polylactosamine chains were significantly increased in SW620/5-fu cells. inhibition of the biosynthesis of polylactosamine by 3'-azidothymidine (aZt) was able to reduce 5-fu tolerance. further studies showed that β3gnt8 expression was also upregulated in 5-fu-resistant cancer cells, and knockdown of β3gnt8 by rna interference reversed 5-fu resistance through, at least partly, by suppressing the formation of polylactosamine. in conclusion, the alteration of β3gnt8 in crc cells correlates with tumor sensitivity to the chemotherapeutic drug and has significant implication for the development of new treatment strategies.

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Increased levels and defective glycosylation of MRPs in ovarian carcinoma cells resistant to oxaliplatin

Cited by 97 publications

References 37 publications

Heterogeneous response of different tumor cell lines to methotrexate-coupled nanoparticles in presence of hyperthermia

Heterogeneous response of different tumor cell lines to methotrexate-coupled nanoparticles in presence of hyperthermia

Methylation status of TUSC3 is a prognostic factor in ovarian cancer

Knockdown of β3GnT8 reverses 5-fluorouracil resistance in human colorectal cancer cells via inhibition the biosynthesis of polylactosamine-type N-glycans

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