Etoposide-Induced Apoptosis in Cancer Cells Can Be Reinforced by an Uncoupled Link between Hsp70 and Caspase-3.

Sverchinsky, Dmitry V.; Nikotina, Alina D.; Komarova, Elena Y.; Mikhaylova, Elena R.; Aksenov, Nikolay D.; Lazarev, Vladimir F.; Mitkevich, Vladimir A.; Suezov, Roman; Druzhilovskiy, Dmitry S.; Poroikov, Vladimir V.; Margulis, Boris A.; Guzhova, Irina V.

The Hsp70 chaperone binds and inhibits proteins implicated in apoptotic signaling including Caspase-3. Induction of apoptosis is an important mechanism of anti-cancer drugs, therefore Hsp70 can act as a protective system in tumor cells against therapeutic agents. In this study we present an assessment of candidate compounds that are able to dissociate the complex of Hsp70 with Caspase-3, and thus sensitize cells to drug-induced apoptosis. Using the PASS program for prediction of biological activity we selected a derivative of benzodioxol (BT44) that is known to affect molecular chaperones and caspases. Drug affinity responsive target stability and microscale thermophoresis assays indicated that BT44 bound to Hsp70 and reduced the chaperone activity. When etoposide was administered, heat shock accompanied with an accumulation of Hsp70 led to an inhibition of etoposide-induced apoptosis. The number of apoptotic cells increased following BT44 administration, and forced Caspase-3 processing. Competitive protein–protein interaction and immunoprecipitation assays showed that BT44 caused dissociation of the Hsp70–Caspase-3 complex, thus augmenting the anti-tumor activity of etoposide and highlighting the potential role of molecular separators in cancer therapy.

HSP70 heat-shock proteins; CASPASES; ETOPOSIDE; APOPTOSIS; CANCER cells

International Journal of Molecular Sciences, 2018, Vol 19, Issue 9, p2519

1661-6596

Academic Journal

10.3390/ijms19092519