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Survivin inhibits excessive autophagy in cancer cells but does so independently of its interaction with LC3.

ABSTRACT: Survivin expression is pivotal to life and death at the cellular level. For the past decade its pro-survival activity has been attributed to its essential role in cell proliferation and its ability to inhibit apoptosis. However, a growing body of evidence suggests that it may also contribute to cell viability through an as yet undefined role in autophagy. We report that survivin overexpression in osteosarcoma (U2OS) cells is associated with increased LC3-II expression, smaller autophagosomes, enlarged lysosomes and reduced autophagic flux. We also demonstrate that survivin binds LC3 directly through a canonical LC3-interacting region (LIR) in its baculovirus inhibitors of apoptosis protein (IAP) repeat BIR domain, mutation of which inhibits the interaction, but does not abrogate its influence on autophagy. Collectively these data suggest that survivin expression restricts autophagic flux, thereby inhibiting late-stage autophagy and preventing cell death, but does so independently of LC3.

SUBMITTER: Humphry NJ

PROVIDER: S-EPMC6215416 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Survivin inhibits excessive autophagy in cancer cells but does so independently of its interaction with LC3.

Humphry Nicola J NJ Wheatley Sally P SP

Biology open 20181022 10

Survivin expression is pivotal to life and death at the cellular level. For the past decade its pro-survival activity has been attributed to its essential role in cell proliferation and its ability to inhibit apoptosis. However, a growing body of evidence suggests that it may also contribute to cell viability through an as yet undefined role in autophagy. We report that survivin overexpression in osteosarcoma (U2OS) cells is associated with increased LC3-II expression, smaller autophagosomes, en ...[more]

PMID: 30348810

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Project description:Posaconazole (POS) has been reported to present potential antitumor activity for glioblastoma (GBM). However, its molecular mechanisms remain unclear. In this study, we found that POS has potent cytotoxicity and inhibits cell viability and proliferation in GBM. In addition, we adopted a sphere formation assay to detect the self-renewal capacity, performed western blotting to measure cancer stem-like cells (CSCs) marker proteins (CD133, SOX2, Nanog and Oct4) and applied flow cytometry to monitor the subpopulation of CD144+/CD33+ cells, and the results all demonstrated that POS can remarkably weaken CSCs stemness. Furthermore, western blotting, immunoflurescence, transmission electron microscopy and acridine orange staining were performed to detect autophagy-related proteins (LC3, SQSTM1, Beclin 1 and Atg5), count the numbers of endogenous LC3 puncta, visually observe the ultrastructural morphology of autophagosomes and judge the formation of acidic vesicular organelles, respectively, and the results validated that POS promotes autophagy induction. Importantly, the suppressive effect of POS on CSCs stemness was partially relieved when autophagy was blocked by the autophagy inhibitor chloroquine (CQ) or Atg5 shRNA. Bioinformatic techniques, including weighted gene coexpression network analysis (WGCNA), gene set difference analysis (GSVA) and KEGG pathway analysis, combined with experimental validations showed that survivin, which is implicated in both autophagy and the stem cell index, is one of the target proteins of POS and that POS weakens CSCs stemness via suppressing the Wnt/β-catenin signaling pathway in GBM. Besides, POS-induced autophagy and the Wnt/β-catenin signaling pathway are negative regulators for each other. Finally, the antitumor activity of POS was confirmed in GBM xenograft models in vivo. Consistent with the in vitro conclusions, POS upregulated the expression of LC3 and decreased the expression of CD133, survivin and β-catenin, as shown by the immunohistochemistry analysis. In summary, this work provides an experimental foundation for exploiting POS as a CSCs-targeting antitumor drug for GBM treatment.

Dataset Information

Survivin inhibits excessive autophagy in cancer cells but does so independently of its interaction with LC3.

Publications

Survivin inhibits excessive autophagy in cancer cells but does so independently of its interaction with LC3.

Similar Datasets

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