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Inhibition of thioredoxin activates mitophagy and overcomes adaptive bortezomib resistance in multiple myeloma.

Publication ,  Journal Article
Zheng, Z; Fan, S; Zheng, J; Huang, W; Gasparetto, C; Chao, NJ; Hu, J; Kang, Y
Published in: J Hematol Oncol
February 27, 2018

BACKGROUND: Although current chemotherapy using bortezomib (Velcade) against multiple myeloma in adults has achieved significant responses and even remission, a majority of patients will develop acquired resistance to bortezomib. Increased thioredoxin level has been reported to be associated with carcinogenesis; however, the role of thioredoxin in bortezomib drug resistance of myeloma remains unclear. METHODS: We generated several bortezomib-resistant myeloma cell lines by serially passaging with increased concentrations of bortezomib over a period of 1.5 years. Thioredoxin expression was measured by real-time PCR and western blot. RESULTS: The role of thioredoxin in the survival of bortezomib-resistant myeloma cells was determined by specific shRNA knockdown in vitro and in vivo. Thioredoxin inhibitor (PX12) was used to determine the effectiveness of thioredoxin inhibition in the treatment of bortezomib-resistant myeloma cells. The effect of thioredoxin inhibition on mitophagy induction was examined. The correlation of thioredoxin expression with patient overall survival was interrogated. Thioredoxin expression was significantly upregulated in bortezomib-resistant myeloma cells and the change correlated with the increase of bortezomib concentration. Thioredoxin gene knockdown using specific shRNA sensitized bortezomib-resistant myeloma cells to bortezomib efficiency in vitro and in vivo. Similarly, pharmacological inhibition with PX12 inhibited the growth of bortezomib-resistant myeloma cells and overcame bortezomib resistance in vitro and in vivo. Furthermore, inhibition of thioredoxin resulted in the activation of mitophagy and blockage of mitophagy prevented the effects of PX12 on bortezomib-resistant myeloma cells, indicating that mitophagy is the important molecular mechanism for the induction of cell death in bortezomib-resistant myeloma cells by PX12. Moreover, inhibition of thioredoxin resulted in downregulation of phosphorylated mTOR and ERK1/2. Finally, thioredoxin was overexpressed in primary myeloma cells isolated from bortezomib-resistant myeloma patients and overexpression of thioredoxin correlated with poor overall survival in patients with multiple myeloma. CONCLUSIONS: Our findings demonstrated that increased thioredoxin plays a critical role in bortezomib resistance in multiple myeloma through mitophagy inactivation and increased mTOR and ERK1/2 phosphorylation. Thioredoxin provides a potential target for clinical therapeutics against multiple myeloma, particularly for bortezomib-resistant/refractory myeloma patients.

Duke Scholars

Published In

J Hematol Oncol

DOI

EISSN

1756-8722

Publication Date

February 27, 2018

Volume

11

Issue

1

Start / End Page

29

Location

England

Related Subject Headings

  • Up-Regulation
  • Thioredoxins
  • Multiple Myeloma
  • Mitophagy
  • Mice, SCID
  • Mice, Inbred NOD
  • Humans
  • Drug Resistance, Neoplasm
  • Cell Line, Tumor
  • Bortezomib
 

Citation

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Zheng, Z., Fan, S., Zheng, J., Huang, W., Gasparetto, C., Chao, N. J., … Kang, Y. (2018). Inhibition of thioredoxin activates mitophagy and overcomes adaptive bortezomib resistance in multiple myeloma. J Hematol Oncol, 11(1), 29. https://doi.org/10.1186/s13045-018-0575-7
Zheng, Zhihong, Shengjun Fan, Jing Zheng, Wei Huang, Cristina Gasparetto, Nelson J. Chao, Jianda Hu, and Yubin Kang. “Inhibition of thioredoxin activates mitophagy and overcomes adaptive bortezomib resistance in multiple myeloma.J Hematol Oncol 11, no. 1 (February 27, 2018): 29. https://doi.org/10.1186/s13045-018-0575-7.
Zheng Z, Fan S, Zheng J, Huang W, Gasparetto C, Chao NJ, et al. Inhibition of thioredoxin activates mitophagy and overcomes adaptive bortezomib resistance in multiple myeloma. J Hematol Oncol. 2018 Feb 27;11(1):29.
Zheng, Zhihong, et al. “Inhibition of thioredoxin activates mitophagy and overcomes adaptive bortezomib resistance in multiple myeloma.J Hematol Oncol, vol. 11, no. 1, Feb. 2018, p. 29. Pubmed, doi:10.1186/s13045-018-0575-7.
Zheng Z, Fan S, Zheng J, Huang W, Gasparetto C, Chao NJ, Hu J, Kang Y. Inhibition of thioredoxin activates mitophagy and overcomes adaptive bortezomib resistance in multiple myeloma. J Hematol Oncol. 2018 Feb 27;11(1):29.
Journal cover image

Published In

J Hematol Oncol

DOI

EISSN

1756-8722

Publication Date

February 27, 2018

Volume

11

Issue

1

Start / End Page

29

Location

England

Related Subject Headings

  • Up-Regulation
  • Thioredoxins
  • Multiple Myeloma
  • Mitophagy
  • Mice, SCID
  • Mice, Inbred NOD
  • Humans
  • Drug Resistance, Neoplasm
  • Cell Line, Tumor
  • Bortezomib