2. Academic Validation
  3. Non-canonical role for the ataxia-telangiectasia-Rad3 pathway in STAT3 activation in human multiple myeloma cells

Non-canonical role for the ataxia-telangiectasia-Rad3 pathway in STAT3 activation in human multiple myeloma cells

  • Cell Oncol (Dordr). 2023 Oct;46(5):1369-1380. doi: 10.1007/s13402-023-00817-6.
Lin Li # 1,  Xiaoyan Hu # 1,  Jewel Nkwocha 1,  Kanika Sharma 1,  Maciej Kmieciak 2,  Hashim Mann 1,  Liang Zhou 1 3,  Steven Grant 4 5
Affiliations

Affiliations

  • 1 Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, P.O. Box 980035, Richmond, VA, 23298, USA.
  • 2 Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
  • 3 Department of Translational Medicine, Asklepios BioPharmaceutical, Inc., Durham, NC, USA.
  • 4 Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, P.O. Box 980035, Richmond, VA, 23298, USA. [email protected].
  • 5 Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA. [email protected].
  • # Contributed equally.
PMID: 37126127 DOI: 10.1007/s13402-023-00817-6
Abstract

Purpose: The goal of this study was to characterize the relationship between ATR and STAT3 interactions in human multiple myeloma (MM) cells.

Methods: Various MM cell lines, including IL-6-dependent cells were exposed to ATR inhibitors and effects on STAT3 Tyr705 and Ser727 were monitored by WB analysis and ImageStream analysis. Parallel studies examined induction of cell death, STAT3 DNA binding activity, and expression of STAT3 downstream targets (BCL-XL, Mcl-1, c-Myc). Validation was obtained in ATR shRNA knock-down cells, and in cells ectopically expressing BCL-XL, Mcl-1, or c-Myc. Analogous studies were performed in primary MM cells and in a MM xenograft model.

Results: Multiple pharmacologic ATR inhibitors inhibited STAT3 Tyr705 (but not Ser727) phosphorylation at low uM concentrations and down-regulated BCL-XL, Mcl-1, c-Myc in association with cell death induction. Compatible results were observed in ATR shRNA knock-down cells. Cell death induced by ATR inhibitors was significantly attenuated in cells ectopically expressing constitutively active STAT3, BCL-XL, Mcl-1, or c-Myc. Concordant results were observed in primary human MM cells and in an in vivo MM xenograft model.

Conclusions: Collectively, these findings argue for a non-canonical role for the ATR kinase in STAT3 activation in MM cells, and suggest that STAT3 inactivation contributes to the lethal actions of ATR inhibitors in MM.

Keywords

ATR; Apoptosis; Myeloma; STAT3.

Figures
Products