Reactivating PTEN to impair glioma stem cells by inhibiting cytosolic iron-sulfur assembly.

in Science translational medicine by Jianxing Yin, Xin Ge, Fangshu Ding, Liuguijie He, Keying Song, Zhumei Shi, Zehe Ge, Junxia Zhang, Jing Ji, Xiefeng Wang, Ningwei Zhao, Chuanjun Shu, Fan Lin, Qianghu Wang, Qigang Zhou, Yuandong Cao, Wentao Liu, Dan Ye, Jeremy N Rich, Xiuxing Wang, Yongping You, Xu Qian

TLDR

  • The study found that a protein called PTEN is important for a type of brain tumor called glioblastoma. The study found that a specific modification to PTEN called succination is important for the growth and survival of glioblastoma cells. The study also found that targeting this modification with a drug called NAC can make glioblastoma cells more sensitive to treatment with other drugs. The study suggests that this could be a new way to treat glioblastoma.

Abstract

Glioblastoma, the most lethal primary brain tumor, harbors glioma stem cells (GSCs) that not only initiate and maintain malignant phenotypes but also enhance therapeutic resistance. Although frequently mutated in glioblastomas, the function and regulation of PTEN in PTEN-intact GSCs are unknown. Here, we found that PTEN directly interacted with MMS19 and competitively disrupted MMS19-based cytosolic iron-sulfur (Fe-S) cluster assembly (CIA) machinery in differentiated glioma cells. PTEN was specifically succinated at cysteine (C) 211 in GSCs compared with matched differentiated glioma cells. Isotope tracing coupled with mass spectrometry analysis confirmed that fumarate, generated by adenylosuccinate lyase (ADSL) in the de novo purine synthesis pathway that is highly activated in GSCs, promoted PTEN C211 succination. This modification abrogated the interaction between PTEN and MMS19, reactivating the CIA machinery pathway in GSCs. Functionally, inhibiting PTEN C211 succination by reexpressing a PTEN C211S mutant, depleting ADSL by shRNAs, or consuming fumarate by the US Food and Drug Administration-approved prescription drug-acetylcysteine (NAC) impaired GSC maintenance. Reexpressing PTEN C211S or treating with NAC sensitized GSC-derived brain tumors to temozolomide and irradiation, the standard-of-care treatments for patients with glioblastoma, by slowing CIA machinery-mediated DNA damage repair. These findings reveal an immediately practicable strategy to target GSCs to treat glioblastoma by combination therapy with repurposed NAC.

Overview

  • The study investigates the role of PTEN in glioblastoma stem cells (GSCs) and its interaction with MMS19 in cytosolic iron-sulfur (Fe-S) cluster assembly (CIA) machinery. The study found that PTEN is specifically succinated at cysteine (C) 211 in GSCs, which abrogates the interaction between PTEN and MMS19, reactivating the CIA machinery pathway in GSCs. The study aims to identify a practical strategy to target GSCs to treat glioblastoma by combination therapy with repurposed NAC. The hypothesis being tested is that PTEN C211 succination plays a critical role in GSC maintenance and therapeutic resistance, and that targeting this modification can sensitize GSC-derived brain tumors to standard-of-care treatments for glioblastoma. The methodology used for the experiment includes the use of isotope tracing coupled with mass spectrometry analysis to confirm the role of fumarate in PTEN C211 succination, and the use of shRNAs and NAC to deplete ADSL and inhibit PTEN C211 succination. The primary objective of the study is to identify a practical strategy to target GSCs to treat glioblastoma by combination therapy with repurposed NAC.

Comparative Analysis & Findings

  • The study compared the outcomes observed under different experimental conditions, specifically the role of PTEN in GSCs and its interaction with MMS19 in CIA machinery. The study found that PTEN is specifically succinated at C211 in GSCs, which abrogates the interaction between PTEN and MMS19, reactivating the CIA machinery pathway in GSCs. The study also found that inhibiting PTEN C211 succination by reexpressing a PTEN C211S mutant, depleting ADSL by shRNAs, or consuming fumarate by the US Food and Drug Administration-approved prescription drug-acetylcysteine (NAC) impaired GSC maintenance. Functionally, reexpressing PTEN C211S or treating with NAC sensitized GSC-derived brain tumors to temozolomide and irradiation, the standard-of-care treatments for patients with glioblastoma, by slowing CIA machinery-mediated DNA damage repair. The key findings of the study are that PTEN C211 succination plays a critical role in GSC maintenance and therapeutic resistance, and that targeting this modification can sensitize GSC-derived brain tumors to standard-of-care treatments for glioblastoma. The study supports the hypothesis that PTEN C211 succination is a potential therapeutic target for glioblastoma.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. The study identifies a practical strategy to target GSCs to treat glioblastoma by combination therapy with repurposed NAC. The study also highlights the importance of PTEN C211 succination in GSC maintenance and therapeutic resistance, and suggests that targeting this modification could be a potential therapeutic target for glioblastoma. The study identifies limitations, such as the need to further validate the findings in animal models and clinical trials. The study suggests future research directions, such as exploring the role of PTEN C211 succination in other types of brain tumors and identifying other potential therapeutic targets for glioblastoma.
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