LW-213 induces cell apoptosis in human cutaneous T-cell lymphomas by activating PERK–eIF2α–ATF4–CHOP axis

Abstract

Cutaneous T-cell lymphoma (CTCL) is characterized by a heterogeneous group of extranodal non-Hodgkin lymphomas, in which monoclonal T lymphocytes infiltrate the skin. LW-213, a derivative of wogonin, was found to induce cell apoptosis in chronic myeloid leukemia (CML). In this study, we investigated the effects of LW-213 on CTCL cells and the underlying mechanisms. We showed that LW-213 (1–25 μM) dose-dependently inhibited human CTCL cell lines (Hut-102, Hut-78, MyLa, and HH) with IC50 values of around 10 μM, meanwhile it potently inhibited primary leukemia cells derived from peripheral blood of T-cell lymphoma patients. We revealed that LW-213-induced apoptosis was accompanied by ROS formation and the release of calcium from endoplasmic reticulum (ER) through IP3R-1channel. LW-213 selectively activated CHOP and induced apoptosis in Hut-102 cells via activating PERK–eIF2α–ATF4 pathway. Interestingly, the degree of apoptosis and expression of ER stress-related proteins were alleviated in the presence of either N-acetyl cysteine (NAC), an ROS scavenger, or 2-aminoethyl diphenylborinate (2-APB), an IP3R-1 inhibitor, implicating ROS/calcium-dependent ER stress in LW-213-induced apoptosis. In NOD/SCID mice bearing Hut-102 cell line xenografts, administration of LW-213 (10 mg/kg, ip, every other day for 4 weeks) markedly inhibited the growth of Hut-102 derived xenografts and prolonged survival. In conclusion, our study provides a new insight into the mechanism of LW-213-induced apoptosis, suggesting the potential of LW-213 as a promising agent against CTCL.

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Fig. 1: LW-213 inhibited cell viability and induced cell apoptosis in CTCL cells.
Fig. 2: LW-213 increased the intracellular levels of calcium and ROS in CTCL cells.
Fig. 3: LW-213 activated the PERK–eIF2α–ATF4 signaling axis in CTCL cells.
Fig. 4: LW-213 induced intrinsic and extrinsic apoptosis in CTCL cells.
Fig. 5
Fig. 6

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81873046, 81830105, 81903647, 81503096, and 81673461), the Drug Innovation Major Project (2017ZX09301014, 2018ZX09711001-003-007, and 2017ZX09101003-005-023), Natural Science Foundation of Jiangsu Province (BK20190560 and BE2018711), Nanjing Medical Science and Technology Development Project (YKK17074), Research and Innovation Project for College Graduates of Jiangsu Province (KYCX18_0803), China Postdoctoral Science Foundation (No. 2018M642373), and “Double First-Class” University project (CPU 2018GF11 and CPU2018GF05).

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XXY designed and performed research, analyzed data, and wrote the paper; HL and MYZ performed research and analyzed data; PH and JRW performed research; YJQ and XYW collected data and performed statistical analysis; HZW and ZYW collected and analyzed data; JYX provided the blood samples; and QG and HH conceptualized the project and directed the experimental design and data analysis.

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Correspondence to Qing-long Guo or Hui Hui.

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Yu, X., Zhu, M., Wang, J. et al. LW-213 induces cell apoptosis in human cutaneous T-cell lymphomas by activating PERK–eIF2α–ATF4–CHOP axis. Acta Pharmacol Sin (2020). https://doi.org/10.1038/s41401-020-0466-7

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Keywords

  • CTCL
  • LW-213
  • wogonin
  • flavonoids
  • ER stress
  • ROS
  • calcium
  • apoptosis
  • NAC
  • 2-APB

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