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2016 ; 7
(16
): 22050-63
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Knock-down of Hdj2/DNAJA1 co-chaperone results in an unexpected burst of
tumorigenicity of C6 glioblastoma cells
#MMPMID26959111
Meshalkina DA
; Shevtsov MA
; Dobrodumov AV
; Komarova EY
; Voronkina IV
; Lazarev VF
; Margulis BA
; Guzhova IV
Oncotarget
2016[Apr]; 7
(16
): 22050-63
PMID26959111
show ga
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.