KPT330 promotes the sensitivity of glioblastoma to olaparib by retaining SQSTM1 in the nucleus and disrupting lysosomal function

Li-Hong Wang; Sen Wei; Ye Yuan; Ming-Jun Zhong; Jiao Wang; Ze-Xuan Yan; Kai Zhou; Tao Luo; Li Liang; Xiu-Wu Bian

doi:10.1080/15548627.2023.2252301

KPT330 promotes the sensitivity of glioblastoma to olaparib by retaining SQSTM1 in the nucleus and disrupting lysosomal function

Autophagy. 2024 Feb;20(2):295-310. doi: 10.1080/15548627.2023.2252301. Epub 2023 Sep 15.

Authors

Li-Hong Wang^{1

2}, Sen Wei², Ye Yuan², Ming-Jun Zhong³, Jiao Wang², Ze-Xuan Yan², Kai Zhou⁴, Tao Luo², Li Liang¹, Xiu-Wu Bian²

Affiliations

¹ Department of Pathology, School of Basic Medical Science, Southern Medical University, Guangzhou, Guangdong, China.
² Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing 400038, China.
³ Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu 610000, China.
⁴ Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.

Abstract

AO: acridine orange; ATM: ATM serine/threonine kinase; CHEK1: checkpoint kinase 1; CHEK2: checkpoint kinase 2; CI: combination index; DMSO: dimethyl sulfoxide; DSBs: double-strand breaks; GBM: glioblastoma; HR: homologous recombination; H2AX: H2A.X variant histone; IHC: immunohistochemistry; LAPTM4B: lysosomal protein transmembrane 4 beta; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PARP: poly(ADP-ribose) polymerase; RAD51: RAD51 recombinase; SQSTM1: sequestosome 1; SSBs: single-strand breaks; RNF168: ring finger protein 168; XPO1: exportin 1.

Keywords: Autophagic flux; KPT330; SQSTM1; glioblastoma; lysosome; olaparib.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autophagy
Glioblastoma*
Humans
Membrane Proteins / metabolism
Oncogene Proteins / metabolism
Phthalazines / pharmacology
Piperazines*
Poly(ADP-ribose) Polymerases / metabolism
Proteins / metabolism
Sequestosome-1 Protein / metabolism
Ubiquitin-Protein Ligases / metabolism

Substances

olaparib
Sequestosome-1 Protein
Phthalazines
Proteins
Poly(ADP-ribose) Polymerases
SQSTM1 protein, human
LAPTM4B protein, human
Membrane Proteins
Oncogene Proteins
RNF168 protein, human
Ubiquitin-Protein Ligases
Piperazines

Grants and funding

This work was supported by General Project of Chongqing Natural Science Foundation (No. cstc2021jcyj msxmX0581), National Key R&D Program of China (2021YFF1201002 to T.L.), Special project of Scientific and Technological Innovation Capability Improvement of Army Military Medical University (2022XQN10), Special project of Scientific and Technological Innovation Capability Improvement of Army Military Medical University (2022XQN11).