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Dynamic analysis of proteomic alterations in response to N-linked glycosylation inhibition in a drug-resistant ovarian carcinoma cell line.

ABSTRACT: Glycosylation inhibition can improve the efficacy of antitumor drugs and enhance the apoptosis of cancer cells, thus holding great potential for cancer treatment. Inhibition of N-glycosylation induces endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), and eventually triggers ER stress-related apoptosis. Unfortunately, the detailed timeline of these cell responses and protein expression alterations related to N-glycosylation inhibition is not explicit yet, and the pathways involved in different stages of N-glycosylation inhibition still need to be characterized. In this study, the dynamic proteome alterations related to N-glycosylation inhibition were investigated by further analyzing our previously published quantitative proteomics data from tunicamycin (TM)-treated ovarian carcinoma (OVCAR-3) cells. The results revealed that N-glycosylation inhibition not only directly affects the expression of glycosylated proteins but also alters an extended scale of proteins. Functional annotation of these altered proteins demonstrated that proteins related to ER stress start changing within 6 h, followed by UPR within 24 h, and eventually ER stress-related apoptosis is triggered after 48 h, indicating the conversion of cellular response from positive to negative. The dynamic proteome data presented here provide important information for better understanding of the significance of N-glycosylation to cell survival and TM-related cancer treatment.

SUBMITTER: Shu J

PROVIDER: S-EPMC7360092 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Dynamic analysis of proteomic alterations in response to N-linked glycosylation inhibition in a drug-resistant ovarian carcinoma cell line.

Shu Jian J Dang Liuyi L Zhang Dandan D Shah Punit P Chen Lijun L Zhang Hui H Sun Shisheng S

The FEBS journal 20190402 8

Glycosylation inhibition can improve the efficacy of antitumor drugs and enhance the apoptosis of cancer cells, thus holding great potential for cancer treatment. Inhibition of N-glycosylation induces endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), and eventually triggers ER stress-related apoptosis. Unfortunately, the detailed timeline of these cell responses and protein expression alterations related to N-glycosylation inhibition is not explicit yet, and the pathways ...[more]

PMID: 30884134

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Project description:Ovarian cancer is one of the most common cancer among women in the world, and chemotherapy remains the principal treatment for patients. However, drug resistance is a major obstacle to the effective treatment of ovarian cancers and the underlying mechanism is not clear. An increased understanding of the mechanisms that underline the pathogenesis of drug resistance is therefore needed to develop novel therapeutics and diagnostic. Herein, we report the comparative analysis of the doxorubicin sensitive OVCAR8 cells and its doxorubicin-resistant variant NCI/ADR-RES cells using integrated global proteomics and N-glycoproteomics. A total of 1525 unique N-glycosite-containing peptides from 740 N-glycoproteins were identified and quantified, of which 253 N-glycosite-containing peptides showed significant change in the NCI/ADR-RES cells. Meanwhile, stable isotope labeling by amino acids in cell culture (SILAC) based comparative proteomic analysis of the two ovarian cancer cells led to the quantification of 5509 proteins. As about 50% of the identified N-glycoproteins are low-abundance membrane proteins, only 44% of quantified unique N-glycosite-containing peptides had corresponding protein expression ratios. The comparison and calibration of the N-glycoproteome versus the proteome classified 14 change patterns of N-glycosite-containing peptides, including 8 up-regulated N-glycosite-containing peptides with the increased glycosylation sites occupancy, 35 up-regulated N-glycosite-containing peptides with the unchanged glycosylation sites occupancy, 2 down-regulated N-glycosite-containing peptides with the decreased glycosylation sites occupancy, 46 down-regulated N-glycosite-containing peptides with the unchanged glycosylation sites occupancy. Integrated proteomic and N-glycoproteomic analyses provide new insights, which can help to unravel the relationship of N-glycosylation and multidrug resistance (MDR), understand the mechanism of MDR, and discover the new diagnostic and therapeutic targets.

Project description:The majority of ovarian cancer patients are diagnosed in late stages of the disease, in which the tumor cells have leaked into the peritoneum and are present as tumorspheres. These tumorspheres are rich in cancer stem-like cells (CSCs), which are resistant to therapy and are a major source of relapse. The purpose of this research was to identify a safe therapeutic approach that could eradicate the peritoneal CSC-rich tumorspheres and inhibit relapse. Highly metastatic ascitic cells (OVASC-1) that are resistant to standard-of-care chemotherapy due to upregulation of MDR1 gene were obtained from a patient with ovarian carcinoma and recurrent disease. CSC-rich tumorspheres were generated, characterized, and treated with different chemotherapeutics. The most effective drug combination that could eradicate tumorspheres at nanomolar levels despite upregulation of MDR1 gene was identified. Luciferase-expressing OVASC-1 cells were implanted in the peritoneum of nude mice and treated with the identified drug combination. The progression of disease, response to therapy and recurrence were studied by quantitative imaging. Toxicity to abdominal tissues was studied by histopathology. Mice implanted with intraperitoneal (IP) OVASC-1 xenografts showed limited response to combination therapy with cisplatin/paclitaxel at the maximum tolerated dose. Despite overexpression of MDR1 on OVASC-1 cells, mice treated with our combination IP low-dose MMAE and SN-38 chemotherapy showed complete response without relapse. No signs of toxicity to abdominal tissues were observed. While MMAE and SN-38 are not administered as free drugs due to their high potency and potential for systemic toxicity, our low-dose localized therapy approach effectively restricted the cytotoxic effects to the tumor cells in the peritoneum. Consequently, maximum efficacy with minimal adverse effects was achieved. These remarkable results with IP low-dose combination chemotherapy encourage investigation into its potential clinical application as either first-line therapy or in cases of acquired resistance to cisplatin and paclitaxel.

Dataset Information

Dynamic analysis of proteomic alterations in response to N-linked glycosylation inhibition in a drug-resistant ovarian carcinoma cell line.

Publications

Dynamic analysis of proteomic alterations in response to N-linked glycosylation inhibition in a drug-resistant ovarian carcinoma cell line.

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