Alterations in the glycoform of cisplatin-resistant human carcinoma cells are caused by defects in the endoplasmic reticulum-associated degradation system

Hiroaki Nakagawa, Miki Ohira, Shunji Hayashi, Shigeaki Abe, Shin Saito, Noriko Nagahori, Kenji Monde, Yasuro Shinohara, Naoki Fujitani, Hirosato Kondo, Shin Ichi Akiyama, Akira Nakagawara, Shin Ichiro Nishimura

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Cisplatin, cis-diamineplatinum-(II) dichloride (CDDP), is one of the most common and valuable chemotherapeutic reagents for various cancers. However, it is well known that tumor cells gain acquired or intrinsic resistance to treatment by this anti-cancer reagent. In spite of extensive efforts using genetic and proteomic approaches, the mechanism underlying CDDP resistance remains unclear. In the present study, we report drastic structural changes in the N-glycans of glycoproteins in CDDP-resistant tumor cells (the KCP-4 cell line obtained from KB-3-1 human carcinoma cells). It was suggested that the CDDP-resistant cells exhibited an increase in one of the high-mannose-type glycans, particularly M8.1. This N-glycan is well known as a tag for the transport of unfolded protein from the endoplasmic reticulum to the lysosome, a process known as endoplasmic reticulum-associated degradation (ERAD) system. The revertant cells (KCP-4R) obtained from the KCP-4 cell line showed almost the same glycoform profile as that of the parental cells, suggesting that N-glycan biosynthesis in tumor cells clearly corresponds to the alteration in the sensitivity against CDDP. Gene expression analysis using a cDNA microarray showed a decrease in the expression of major histocompatibility complex (MHC) proteins in the resistant cells. MHC proteins form a complex with lysosome-degradated proteins and are presented on the cell surface. These results suggest that CDDP tolerance in KCP-4 cells is caused by a defect in the ERAD system.

Original languageEnglish
Pages (from-to)295-301
Number of pages7
JournalCancer Letters
Volume270
Issue number2
DOIs
Publication statusPublished - Nov 8 2008
Externally publishedYes

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Endoplasmic Reticulum-Associated Degradation
Cisplatin
Carcinoma
Polysaccharides
Neoplasms
Lysosomes
Major Histocompatibility Complex
Cell Line
Proteins
Mannose
Oligonucleotide Array Sequence Analysis
Endoplasmic Reticulum
Proteomics
Glycoproteins
Carrier Proteins

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Alterations in the glycoform of cisplatin-resistant human carcinoma cells are caused by defects in the endoplasmic reticulum-associated degradation system. / Nakagawa, Hiroaki; Ohira, Miki; Hayashi, Shunji; Abe, Shigeaki; Saito, Shin; Nagahori, Noriko; Monde, Kenji; Shinohara, Yasuro; Fujitani, Naoki; Kondo, Hirosato; Akiyama, Shin Ichi; Nakagawara, Akira; Nishimura, Shin Ichiro.

In: Cancer Letters, Vol. 270, No. 2, 08.11.2008, p. 295-301.

Research output: Contribution to journalArticle

Nakagawa, H, Ohira, M, Hayashi, S, Abe, S, Saito, S, Nagahori, N, Monde, K, Shinohara, Y, Fujitani, N, Kondo, H, Akiyama, SI, Nakagawara, A & Nishimura, SI 2008, 'Alterations in the glycoform of cisplatin-resistant human carcinoma cells are caused by defects in the endoplasmic reticulum-associated degradation system', Cancer Letters, vol. 270, no. 2, pp. 295-301. https://doi.org/10.1016/j.canlet.2008.05.019
Nakagawa, Hiroaki ; Ohira, Miki ; Hayashi, Shunji ; Abe, Shigeaki ; Saito, Shin ; Nagahori, Noriko ; Monde, Kenji ; Shinohara, Yasuro ; Fujitani, Naoki ; Kondo, Hirosato ; Akiyama, Shin Ichi ; Nakagawara, Akira ; Nishimura, Shin Ichiro. / Alterations in the glycoform of cisplatin-resistant human carcinoma cells are caused by defects in the endoplasmic reticulum-associated degradation system. In: Cancer Letters. 2008 ; Vol. 270, No. 2. pp. 295-301.
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AU - Abe, Shigeaki

AU - Saito, Shin

AU - Nagahori, Noriko

AU - Monde, Kenji

AU - Shinohara, Yasuro

AU - Fujitani, Naoki

AU - Kondo, Hirosato

AU - Akiyama, Shin Ichi

AU - Nakagawara, Akira

AU - Nishimura, Shin Ichiro

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AB - Cisplatin, cis-diamineplatinum-(II) dichloride (CDDP), is one of the most common and valuable chemotherapeutic reagents for various cancers. However, it is well known that tumor cells gain acquired or intrinsic resistance to treatment by this anti-cancer reagent. In spite of extensive efforts using genetic and proteomic approaches, the mechanism underlying CDDP resistance remains unclear. In the present study, we report drastic structural changes in the N-glycans of glycoproteins in CDDP-resistant tumor cells (the KCP-4 cell line obtained from KB-3-1 human carcinoma cells). It was suggested that the CDDP-resistant cells exhibited an increase in one of the high-mannose-type glycans, particularly M8.1. This N-glycan is well known as a tag for the transport of unfolded protein from the endoplasmic reticulum to the lysosome, a process known as endoplasmic reticulum-associated degradation (ERAD) system. The revertant cells (KCP-4R) obtained from the KCP-4 cell line showed almost the same glycoform profile as that of the parental cells, suggesting that N-glycan biosynthesis in tumor cells clearly corresponds to the alteration in the sensitivity against CDDP. Gene expression analysis using a cDNA microarray showed a decrease in the expression of major histocompatibility complex (MHC) proteins in the resistant cells. MHC proteins form a complex with lysosome-degradated proteins and are presented on the cell surface. These results suggest that CDDP tolerance in KCP-4 cells is caused by a defect in the ERAD system.

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