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Kinome-wide synthetic lethal screen identifies PANK4 as a modulator of temozolomide resistance in glioblastoma

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posted on 2024-02-21, 10:47 authored by Viviana VellaViviana Vella, Angeliki Ditsiou, Anna Chalari, Murat Eravci, Sarah K Wooller, Teresa Gagliano, Cecilia Bani, Emanuela Kerschbamer, Christos Karakostas, Bin Xu, Yongchang Zhang, Frances PearlFrances Pearl, Georgios GiamasGeorgios Giamas, et al.
Temozolomide (TMZ) represents the cornerstone of therapy for glioblastoma (GBM). However, acquisition of resistance limits its therapeutic potential. The human kinome is an undisputable source of druggable targets, still, current knowledge remains confined to a limited fraction of it, with a multitude of under-investigated proteins yet to be characterized. Here, following a kinome-wide RNAi screen, pantothenate kinase 4 (PANK4) isuncovered as a modulator of TMZ resistance in GBM. Validation of PANK4 across various TMZ-resistant GBM cell models, patient-derived GBM cell lines, tissue samples, as well as in vivo studies, corroborates the potential translational significance of these findings. Moreover, PANK4 expression is induced during TMZ treatment, and its expression is associated with a worse clinical outcome. Furthermore, a Tandem Mass Tag (TMT)-based quantitative proteomic approach, reveals that PANK4 abrogation leads to a significant downregulation of a host of proteins with central roles in cellular detoxification and cellular response to oxidative stress. More specifically, as cells undergo genotoxic stress during TMZ exposure, PANK4 depletion represents a crucial event that can lead to accumulation of intracellular reactive oxygen species (ROS) and subsequent cell death. Collectively, a previously unreported role for PANK4 in mediating therapeutic resistance to TMZ in GBM is unveiled.

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Publication status

  • Published

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  • Published version

Journal

Advanced Science

ISSN

2198-3844

Publisher

Wiley

Article number

e2306027

Department affiliated with

  • Biochemistry Publications

Institution

University of Sussex

Full text available

  • Yes

Peer reviewed?

  • Yes

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