Pharmacological inhibition of uncontrolled cell growth with small-molecule inhibitors is a potential strategy for treating glioblastoma multiforme (GBM), the most malignant primary brain cancer. We showed that the synthetic small-molecule KHS101 promoted tumor cell death in diverse GBM cell models, independent of their tumor subtype, and without affecting the viability of noncancerous brain cell lines. KHS101 exerted cytotoxic effects by disrupting the mitochondrial chaperone heat shock protein family D member 1 (HSPD1). In GBM cells, KHS101 promoted aggregation of proteins regulating mitochondrial integrity and energy metabolism. Mitochondrial bioenergetic capacity and glycolytic activity were selectively impaired in KHS101-treated GBM cells. In two intracranial patient-derived xenograft tumor models in mice, systemic administration of KHS101 reduced tumor growth and increased survival without discernible side effects. These findings suggest that targeting of HSPD1-dependent metabolic pathways might be an effective strategy for treating GBM.

Pollen grains transport the sperm cells through the style tissue via a fast growing pollen tube to the ovaries where fertilisation takes place. This tube growth process requires a precisely regulated network of cellular as well as molecular courses of events including the activity of the plasma membrane H + ATPase (PM H + ATPase), which is known to be regulated by reversible protein phosphorylation and subsequent binding of 14-3-3 isoforms. Immunodetection of the phosphorylated penultimate threonine residue of the pollen PM H + ATPase LilHA1 of Lilium longiflorum pollen revealed a sudden increase in phosphorylation with the start of pollen tube growth. In addition to phosphorylation, pH modulated the binding of 14-3-3 isoforms to the regulatory domain (R domain) of the H + ATPase, whereas metabolic components had only little effects on 14-3-3 binding as tested in in vitro assays using recombinant produced 14-3-3 isoforms and phosphomimicking substitutions of the threonine residue. In consequence of these results, local H + influxes and effluxes as well as pH gradients in the pollen tube tip are generated by localised regulation of the H + ATPase activity and not only by heterogeneous distribution in the plasma membrane.

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