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

Autor: Sverchinsky DV; Laboratory of Cell Protection Mechanisms, Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Ave. 4, St., Petersburg 194064, Russia. dsverchinsky@gmail.com., Nikotina AD; Laboratory of Cell Protection Mechanisms, Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Ave. 4, St., Petersburg 194064, Russia. nikotina.ad@gmail.com., Komarova EY; Laboratory of Cell Protection Mechanisms, Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Ave. 4, St., Petersburg 194064, Russia. elpouta@yahoo.com., Mikhaylova ER; Laboratory of Cell Protection Mechanisms, Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Ave. 4, St., Petersburg 194064, Russia. mikhailovaer@yandex.ru., Aksenov ND; Laboratory of Cell Protection Mechanisms, Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Ave. 4, St., Petersburg 194064, Russia. aksenovn@gmail.com., Lazarev VF; Laboratory of Cell Protection Mechanisms, Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Ave. 4, St., Petersburg 194064, Russia. vl.lazarev@gmail.com., Mitkevich VA; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilova, Moscow 119991, Russia. mitkevich@gmail.com., Suezov R; Laboratory of Cell Protection Mechanisms, Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Ave. 4, St., Petersburg 194064, Russia. roman.suezov@gmail.com., Druzhilovskiy DS; Institute of Biomedical Chemistry, Pogodinskaya str., 10, bldg. 8, Moscow 119121, Russia. dmitry.druzhilovsky@ibmc.msk.ru., Poroikov VV; Institute of Biomedical Chemistry, Pogodinskaya str., 10, bldg. 8, Moscow 119121, Russia. vvp1951@yandex.ru., Margulis BA; Laboratory of Cell Protection Mechanisms, Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Ave. 4, St., Petersburg 194064, Russia. margulis@incras.ru., Guzhova IV; Laboratory of Cell Protection Mechanisms, Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Ave. 4, St., Petersburg 194064, Russia. irina.guzh@gmail.com.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2018 Aug 25; Vol. 19 (9). Date of Electronic Publication: 2018 Aug 25.
DOI: 10.3390/ijms19092519
Abstrakt: 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.
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje