Reduced O-GlcNAcylation of SNAP-23 promotes cisplatin resistance by inducing exosome secretion in ovarian cancer

  • Cell Death Discov. 2021 May 18;7(1):112. doi: 10.1038/s41420-021-00489-x.
Luomeng Qian   #  1 ,  Xiaoshan Yang   #  2 ,  Shaohui Li   #  3 ,  Hang Zhao  4 ,  Yunge Gao  1 ,  Shuhui Zhao  1 ,  Xiaohui Lv  1 ,  Xiyuan Zhang  1 ,  Lingxia Li  1 ,  Lianghao Zhai  1 ,  Fuxing Zhou  5 ,  Biliang Chen  6
Affiliations
  • 1. Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
  • 2. State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
  • 3. Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
  • 4. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
  • 5. Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. [email protected].
  • 6. Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. [email protected].
  • # Contributed equally.
PMID: 34001861 DOI: 10.1038/s41420-021-00489-x
Abstract

Exosomes have been associated with chemoresistance in various cancers, but such a role in ovarian Cancer is not yet clear. Here, using in vitro cell-based and in vivo mouse model experiments, we show that downregulation of O-GlcNAcylation, a key post-translational protein modification, promotes exosome secretion. This increases exosome-mediated efflux of cisplatin from Cancer cells resulting in chemoresistance. Mechanistically, our data indicate that downregulation of O-GlcNAclation transferase (OGT) reduces O-GlcNAclation of SNAP-23. Notably, O-GlcNAcylation of SNAP-23 is vital for regulating exosome release in ovarian Cancer cells. Reduced O-GlcNAclation of SNAP-23 subsequently promotes the formation of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex consisting of SNAP-23, VAMP8, and Stx4 proteins. This enhances exosome release causing chemoresistance by increasing the efflux of intracellular cisplatin.

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