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Smurf1 Suppression Enhances Temozolomide Chemosensitivity in Glioblastoma by Facilitating PTEN Nuclear Translocation
Lei Dong1, Yang Li1, Liqun Liu1
1School of Life Science, Beijing Institute of Technology, Beijing 100081, China.
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.
Insights
Smurf1 facilitates tumor suppressor PTEN
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- PTEN protein suppresses the PI3K/Akt pathway in the cytoplasm and maintains DNA stability in the nucleus.
- PTEN's role in chemoresistance to temozolomide (TMZ) in glioblastoma (GB) is crucial but not fully understood.
- The interconnected mechanisms of PTEN in both cellular compartments regarding TMZ resistance require elucidation.
Purpose of the Study:
- To investigate the mechanisms underlying PTEN's dual role in TMZ resistance in glioblastoma.
- To identify the specific molecular players involved in PTEN's nuclear import and cytoplasmic function under TMZ treatment.
- To explore the potential of targeting these mechanisms for overcoming chemoresistance.
Main Methods:
- Utilized ubiquitylation assays to study PTEN modification by Smurf1.
- Investigated PTEN nuclear translocation using cell imaging techniques.
- Assessed DNA damage and PI3K/Akt pathway activation in response to Smurf1 modulation.
- Employed a nuclear-import-deficient PTEN mutant (K289E) to study cytoplasmic functions.
Main Results:
- TMZ treatment induces PTEN nuclear import, a process dependent on PTEN ubiquitylation by Smurf1.
- Suppression of Smurf1 inhibits TMZ-induced PTEN nuclear translocation, leading to enhanced DNA damage.
- Smurf1 degrades cytoplasmic PTEN K289E, consequently activating the PI3K/Akt pathway during TMZ treatment.
- Smurf1 plays a dual role, promoting PTEN's nuclear DNA repair function and cytoplasmic PI3K/Akt pathway activation.
Conclusions:
- Smurf1 is a key regulator connecting PTEN's cytoplasmic and nuclear functions to promote TMZ resistance in glioblastoma.
- Targeting Smurf1 presents a potential therapeutic strategy to overcome temozolomide resistance in glioblastoma patients with wild-type PTEN.
- Understanding Smurf1-PTEN interactions offers new insights into glioblastoma chemoresistance mechanisms.
