Smurf1 Suppression Enhances Temozolomide Chemosensitivity in Glioblastoma by Facilitating PTEN Nuclear Translocation

Cells. 2022 Oct 20;11(20):3302. doi: 10.3390/cells11203302.

Abstract

The tumor suppressor PTEN mainly inhibits the PI3K/Akt pathway in the cytoplasm and maintains DNA stability in the nucleus. The status of PTEN remains therapeutic effectiveness for chemoresistance of the DNA alkylating agent temozolomide (TMZ) in glioblastoma (GB). However, the underlying mechanisms of PTEN's interconnected role in the cytoplasm and nucleus in TMZ resistance are still unclear. In this study, we report that TMZ-induced PTEN nuclear import depends on PTEN ubiquitylation modification by Smurf1. The Smurf1 suppression decreases the TMZ-induced PTEN nuclear translocation and enhances the DNA damage. In addition, Smurf1 degrades cytoplasmic PTEN K289E (the nuclear-import-deficient PTEN mutant) to activate the PI3K/Akt pathway under TMZ treatment. Altogether, Smurf1 interconnectedly promotes PTEN nuclear function (DNA repair) and cytoplasmic function (activation of PI3K/Akt pathway) to resist TMZ. These results provide a proof-of-concept demonstration for a potential strategy to overcome the TMZ resistance in PTEN wild-type GB patients by targeting Smurf1.

Keywords: PTEN; TMZ; drug resistance; glioblastoma; smurf1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylating Agents / pharmacology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Glioblastoma* / metabolism
  • Humans
  • PTEN Phosphohydrolase
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt / metabolism
  • Temozolomide / pharmacology
  • Temozolomide / therapeutic use
  • Ubiquitin-Protein Ligases

Substances

  • Temozolomide
  • Proto-Oncogene Proteins c-akt
  • Phosphatidylinositol 3-Kinases
  • Alkylating Agents
  • PTEN protein, human
  • PTEN Phosphohydrolase
  • SMURF1 protein, human
  • Ubiquitin-Protein Ligases

Grants and funding

This research was funded by the Natural Science Foundation of Beijing Municipality, grant number Z190018; National Natural Science Foundation of China, grant number U21A20200 and 81870123; Beijing Institute of Technology Research Fund Program for Young Scholars, grant number XSQD-202110002; and the National Science Foundation for Young Scientists of China, grant number 81902545.