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Stellettin B renders glioblastoma vulnerable to poly (ADP-ribose) polymerase inhibitors via suppressing homology-directed repair

ABSTRACT: Glioblastoma (GBM) is the most malignant tumor of the central nervous system. Current first-line post-surgery regimens for GBM including radiotherapy and temozolomide (TMZ) chemotherapy show very limited efficacy, with a median overall survival of only 15 months. Therefore, the development of therapeutic strategies and novel agents for GBM patients is an urgent need. Historically, natural products have played a key role in drug discovery, especially in the field of cancer treatment. We previously isolated stellettin B (STELB), an isomalabaricane triterpenoid, from marine sponge Jaspis stellifera and reported its remarkable and specific anticancer activities, which has attracted wide attention. Recently, a series of stellettins has been totally synthesized, removing a major barrier in drug development for the whole family of these chemicals. Notably, previous structure-activity relationship (SAR) studies have shown that stellettin A, B, and E share a singular trans-syn-trans perhydrobenz[e]indene core that is indispensable for their anticancer effects. However, the specific mechanism and its role in regulating tumor biology remain largely unknown.

ORGANISM(S): Homo Sapiens

SUBMITTER: Dexin Kong

PROVIDER: PXD037301 | iProX | Tue Oct 11 00:00:00 BST 2022

REPOSITORIES: iProX

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Stellettin B renders glioblastoma vulnerable to poly (ADP-ribose) polymerase inhibitors via suppressing homology-directed repair.

Peng Xin X Wang Yingying Y Zhang Shaolu S Tao Zhennan Z Dai Yuxiang Y Claret Francois X FX Elkabets Moshe M Lin Hou-Wen HW Chen Zhe-Sheng ZS Kong Dexin D

Signal transduction and targeted therapy 20230322 1

PMID: 36944633

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Project description:Glioblastoma (GBM) carries a dismal prognosis largely due to acquired resistance to the standard treatment, which incorporates the chemotherapy temozolomide (TMZ). Inhibiting the proteasomal pathway is an emerging strategy, where combination treatments are under clinical investigation. We hypothesized that pre-treatment of GBM with bortezomib (BTZ) might sensitize glioblastoma to TMZ by abolishing autophagy survival signals to augment DNA damage and apoptosis. P3 patient-derived GBM cells as well as the tumor cell lines U87, HF66, A172 and T98G were investigated for clonogenic survival after single or combined treatment with TMZ and BTZ in vitro. Change in autophagic flux was examined after experimental treatments in conjunction with inhibitors of autophagy or downregulation of autophagy-related genes -5 and -7 (ATG5 and ATG7, respectively). Autophagic flux was increased in TMZ-resistant P3 and T98G cells as indicated by diminished levels of the autophagy markers LC3A/B-II and increased STX17, higher protein degradation and no formation of p62 bodies nor induction of apoptosis. In contrast, BTZ treatment attenuated ULK1 mRNA, total and phosphorylated protein, and accumulated LC3A/B-II, p62 and autophagosomes analogously to Baf1 and chloroquine autophagy inhibitors. These autophagosomes did not fuse with lysosomes, indicated by attenuated STX17 expression and reduced degradation of long-lived proteins, which culminated in enhanced caspase-3/8 dependent apoptosis. BTZ synergistically enhanced TMZ efficacy, attenuated tumor cell proliferation, triggered ATM/Chk2 DNA damage signalling to further augment caspase-3/8 mediated apoptosis in the TMZ resistant P3 and T98G GBM cells. Genetic or chemical inhibition of autophagy (with CRISPR-CAs9 ATG5, ATG7 shRNA, MRT68921 or VPS34-IN1) abrogated BTZ efficacy and rescued BTZ+ TMZ treated GBM cells from death. We conclude that Bortezomib ameliorates temozolomide resistance through ATG5/7-dependent abrogated autophagic flux and may be amenable in combination treatment regimens for TMZ refractory GBM patients.

Dataset Information

Stellettin B renders glioblastoma vulnerable to poly (ADP-ribose) polymerase inhibitors via suppressing homology-directed repair

Publications

Stellettin B renders glioblastoma vulnerable to poly (ADP-ribose) polymerase inhibitors via suppressing homology-directed repair.

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