title: Role of mitochondrial network stabilisation by a human small heat shock protein in tumour malignancy.
abstract: Previously, we found that the unconventional small human heat-shock protein HSPB11 inhibits cell death by HSP90 mediated cholesterol-rich membrane microdomain dependent activation of phosphatidylinositol-3 kinase/protein kinase B pathway and by stabilising the mitochondrial membrane systems. Also, progressive cytoplasmic expression of HSPB11 correlated with brain tumor malignancy. In the present study we investigated how cytoplasmic abundance of HSPB11 augments tumor malignancy. We up- and downregulated the cytoplasmic level of HSPB11 before paclitaxel exposure in NIH3T3 and HeLa cells, which normally express low and high levels, respectively, of the HSPB11 protein. We examined the paclitaxel-mediated induction of cell death, mitochondrial fission, HSPB11 mitochondrial translocation and inhibitory phosphorylation of dynamin-like protein-1 (DLP1). We found that increasing cytoplasmic abundance of HSPB11 in NIH3T3 cells protected against paclitaxel-induced apoptosis, while suppressing HSPB11 in HeLa cells sensitised the cells toward paclitaxel. Also, paclitaxel enhanced mitochondrial translocation of HSPB11 in wild type HeLa but not in NIH3T3 cells. More importantly, increased cytoplasmic level of HSPB11 in NIH3T3 cells enhanced the inhibitory phosphorylation of DLP1 and attenuated paclitaxel-induced mitochondrial fission. All these results suggest that increased cytoplasmic abundance of HSPB11 augments inhibitory phosphorylation of DLP1 thereby reduces mitochondrial fission that eventually leads to decreased apoptosis. This novel mechanism may explain the resistance to apoptosis and increased malignancy of HSPB11-overexpressing tumours. The clinical significance of this mechanism has already been highlighted by the finding that the kinase inhibitor tyrphostin A9 induces cancer cell death by DLP1-mediated mitochondrial fragmentation.
authors: 1. Department of Biochemistry and Medical Chemistry, University of Pécs Medical School, 12 Szigeti St., H-7624 Pécs, Hungary;
authors: Zsuzsanna
authors: Z
authors: Turi
authors: 1. Department of Biochemistry and Medical Chemistry, University of Pécs Medical School, 12 Szigeti St., H-7624 Pécs, Hungary;
authors: Eniko
authors: E
authors: Hocsak
authors: 1. Department of Biochemistry and Medical Chemistry, University of Pécs Medical School, 12 Szigeti St., H-7624 Pécs, Hungary;
authors: Boglarka
authors: B
authors: Racz
authors: 1. Department of Biochemistry and Medical Chemistry, University of Pécs Medical School, 12 Szigeti St., H-7624 Pécs, Hungary;
authors: Aliz
authors: A
authors: Szabo
authors: 2. Department of Medical Biology , University of Pécs Medical School, 12 Szigeti St., H-7624 Pécs, Hungary;
authors: Andras
authors: A
authors: Balogh
authors: 1. Department of Biochemistry and Medical Chemistry, University of Pécs Medical School, 12 Szigeti St., H-7624 Pécs, Hungary; ; 3. MTA-PTE Nuclear-Mitochondrial Interactions Research Group, University of Pécs Medical School, 12 Szigeti St., H-7624 Pécs, Hungary; ; 4. Szentagothai Research Centre, 34 Ifjusag St., H-7624 Pécs, Hungary.
authors: Balazs
authors: B
authors: Sumegi
authors: 1. Department of Biochemistry and Medical Chemistry, University of Pécs Medical School, 12 Szigeti St., H-7624 Pécs, Hungary; ; 3. MTA-PTE Nuclear-Mitochondrial Interactions Research Group, University of Pécs Medical School, 12 Szigeti St., H-7624 Pécs, Hungary; ; 4. Szentagothai Research Centre, 34 Ifjusag St., H-7624 Pécs, Hungary.
authors: Ferenc
authors: F
authors: Gallyas
keywords: DLP1; HSPB11; HeLa; apoptosis; cytoprotection; mitochondrial fission; sHSP; tumour malignancy.