Rheostatic CD44 isoform expression and its association with oxidative stress in human malignant mesothelioma

Shan Hwu Chew, Yasumasa Okazaki, Shinya Akatsuka, Shenqi Wang, Li Jiang, Yuuki Ohara, Fumiya Ito, Hideyuki Saya, Yoshitaka Sekido, Shinya Toyokuni

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

CD44 exists as a standard (CD44s) isoform and different variant isoforms (CD44v) due to alternative splicing. While the complex nature of these different isoforms has not been fully elucidated, CD44v expression has been shown to exert oncogenic effects by promoting tumor progression, metastasis and resistance of tumor cells to chemotherapy. One of the CD44v isoforms, CD44v8-10, was recently shown to protect cancer cells from oxidative stress by increasing the synthesis of glutathione (GSH). However, data regarding CD44 isoform expression in malignant mesothelioma (MM) are still lacking. Here, we show that most of the MM cell lines express both the CD44s and CD44v isoforms, in contrast to non-tumorigenic mesothelial cells, which express only CD44s. Moreover, we show here that these MM cell lines are positive for CD44 variable exon 9, with CD44v8-10 among the variant isoforms expressed. The expression of CD44 variable exon 9 was found to be statistically associated with NF2 inactivation, a common occurrence in MM. Knockdown of CD44 reduced the protein level of xCT, a cystine transporter, and increased oxidative stress. However, an increase in GSH was also observed and was associated with enhanced chemoresistance in CD44-knockdown cells. Increased GSH was mediated by the Nrf2/AP-1-induced upregulation of GCLC, a subunit of the enzyme catalyzing GSH synthesis. Our results thus suggest that the response to CD44 depletion is cell type-dependent and, in cases such as MM cells, compensatory pathway(s) might be activated rheostatically to account for the loss of CD44 and counteract enhanced oxidative stress.

Original languageEnglish
Pages (from-to)91-99
Number of pages9
JournalFree Radical Biology and Medicine
Volume106
DOIs
Publication statusPublished - 2017 May 1

Fingerprint

Oxidative stress
Protein Isoforms
Oxidative Stress
Association reactions
Cells
Tumors
Exons
Cell Line
Neoplasms
Chemotherapy
Cystine
Transcription Factor AP-1
Alternative Splicing
Malignant Mesothelioma
Glutathione
Up-Regulation
Neoplasm Metastasis
Drug Therapy
Enzymes

Keywords

  • CD44
  • Glutathione
  • Malignant mesothelioma
  • Nrf2
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Rheostatic CD44 isoform expression and its association with oxidative stress in human malignant mesothelioma. / Chew, Shan Hwu; Okazaki, Yasumasa; Akatsuka, Shinya; Wang, Shenqi; Jiang, Li; Ohara, Yuuki; Ito, Fumiya; Saya, Hideyuki; Sekido, Yoshitaka; Toyokuni, Shinya.

In: Free Radical Biology and Medicine, Vol. 106, 01.05.2017, p. 91-99.

Research output: Contribution to journalArticle

Chew, Shan Hwu ; Okazaki, Yasumasa ; Akatsuka, Shinya ; Wang, Shenqi ; Jiang, Li ; Ohara, Yuuki ; Ito, Fumiya ; Saya, Hideyuki ; Sekido, Yoshitaka ; Toyokuni, Shinya. / Rheostatic CD44 isoform expression and its association with oxidative stress in human malignant mesothelioma. In: Free Radical Biology and Medicine. 2017 ; Vol. 106. pp. 91-99.
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AU - Chew, Shan Hwu

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AU - Akatsuka, Shinya

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AU - Jiang, Li

AU - Ohara, Yuuki

AU - Ito, Fumiya

AU - Saya, Hideyuki

AU - Sekido, Yoshitaka

AU - Toyokuni, Shinya

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AB - CD44 exists as a standard (CD44s) isoform and different variant isoforms (CD44v) due to alternative splicing. While the complex nature of these different isoforms has not been fully elucidated, CD44v expression has been shown to exert oncogenic effects by promoting tumor progression, metastasis and resistance of tumor cells to chemotherapy. One of the CD44v isoforms, CD44v8-10, was recently shown to protect cancer cells from oxidative stress by increasing the synthesis of glutathione (GSH). However, data regarding CD44 isoform expression in malignant mesothelioma (MM) are still lacking. Here, we show that most of the MM cell lines express both the CD44s and CD44v isoforms, in contrast to non-tumorigenic mesothelial cells, which express only CD44s. Moreover, we show here that these MM cell lines are positive for CD44 variable exon 9, with CD44v8-10 among the variant isoforms expressed. The expression of CD44 variable exon 9 was found to be statistically associated with NF2 inactivation, a common occurrence in MM. Knockdown of CD44 reduced the protein level of xCT, a cystine transporter, and increased oxidative stress. However, an increase in GSH was also observed and was associated with enhanced chemoresistance in CD44-knockdown cells. Increased GSH was mediated by the Nrf2/AP-1-induced upregulation of GCLC, a subunit of the enzyme catalyzing GSH synthesis. Our results thus suggest that the response to CD44 depletion is cell type-dependent and, in cases such as MM cells, compensatory pathway(s) might be activated rheostatically to account for the loss of CD44 and counteract enhanced oxidative stress.

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