title: Knock-down of Hdj2/DNAJA1 co-chaperone results in an unexpected burst of tumorigenicity of C6 glioblastoma cells.
abstract: The chaperone system based on Hsp70 and proteins of the DnaJ family is known to protect tumor cells from a variety of cytotoxic factors, including anti-tumor therapy. To analyze whether this also functions in a highly malignant brain tumor, we knocked down the expression of Hsp70 (HSPA1A) and its two most abundant co-chaperones, Hdj1 (DNAJB1) and Hdj2 (DNAJA1) in a C6 rat glioblastoma cell line. As expected, tumor depletion of Hsp70 caused a substantial reduction in its growth rate and increased the survival of tumor-bearing animals, whereas the reduction of Hdj1 expression had no effect. Unexpectedly, a reduction in the expression of Hdj2 led to the enhanced aggressiveness of the C6 tumor, demonstrated by its rapid growth, metastasis formation and a 1.5-fold reduction in the lifespan of tumor-bearing animals. The in vitro reduction of Hdj2 expression reduced spheroid density and simultaneously enhanced the migration and invasion of C6 cells. At the molecular level, a knock-down of Hdj2 led to the relocation of N-cadherin and the enhanced activity of metalloproteinases 1, 2, 8 and 9, which are markers of highly malignant cancer cells. The changes in the actin cytoskeleton in Hdj2-depleted cells indicate that the protein is also important for prevention of the amoeboid-like transition of tumor cells. The results of this study uncover a completely new role for the Hdj2 co-chaperone in tumorigenicity and suggest that the protein is a potential drug target.
authors.affiliation: Institute of Cytology of Russian Academy of Sciences, St. Petersburg 194064, Russia.
authors.forename: Darya A
authors.initials: DA
authors.lastname: Meshalkina
authors.affiliation: Institute of Cytology of Russian Academy of Sciences, St. Petersburg 194064, Russia.|First I.P. Pavlov State Medical University of St. Petersburg, St. Petersburg 197022, Russia.
authors.forename: Maxim A
authors.initials: MA
authors.lastname: Shevtsov
authors.affiliation: Institute of Macromolecular Compounds of the Russian Academy of Sciences, St. Petersburg 199004, Russia.
authors.forename: Anatoliy V
authors.initials: AV
authors.lastname: Dobrodumov
authors.affiliation: Institute of Cytology of Russian Academy of Sciences, St. Petersburg 194064, Russia.
authors.forename: Elena Y
authors.initials: EY
authors.lastname: Komarova
authors.affiliation: Institute of Cytology of Russian Academy of Sciences, St. Petersburg 194064, Russia.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Voronkina
authors.affiliation: Institute of Cytology of Russian Academy of Sciences, St. Petersburg 194064, Russia.
authors.forename: Vladimir F
authors.initials: VF
authors.lastname: Lazarev
authors.affiliation: Institute of Cytology of Russian Academy of Sciences, St. Petersburg 194064, Russia.
authors.forename: Boris A
authors.initials: BA
authors.lastname: Margulis
authors.affiliation: Institute of Cytology of Russian Academy of Sciences, St. Petersburg 194064, Russia.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Guzhova
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000473:pathology*; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D008297:Male; D009361:Neoplasm Invasiveness / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C097210:Hspa1a protein, rat
keywords: Hdj2; Hsp70; glioblastoma; metastases; tumorigenicity