Rearrangement of the Cell Chaperone Machinery in Human Fibrosarcoma HT1080 Cells With the Knocked-Out HSP90AA1 Gene Encoding Hsp90α.
Two isoforms of the 90-kDa heat shock protein (Hsp90), stress-inducible Hsp90α and constitutively expressed Hsp90β, function in mammalian cells as molecular chaperones that promote the folding of specific client proteins involved in essential cellular processes and regulatory pathways. A number of Hsp90 client proteins take part in cancer progression, and the inhibition of Hsp90 induces the degradation of oncogenic client proteins and cancer cell death. Hsp90 inhibitors specific for individual Hsp90 isoforms have a significant potential for the development of anticancer therapeutics due to reduced toxicity. Cells with knocked-out genes encoding Hsp90 isoforms represent excellent cellular models to investigate the rearrangement of the cell chaperone machinery in response to the suppression/loss of the Hsp90 isoforms.
Recently, we have shown that the knockout of the HSP90AA1 gene encoding Hsp90α in human fibrosarcoma HT1080 cells does not affect basic cellular processes in normal and stressful conditions, which suggests an adaptation of the cell chaperone machinery to the loss of Hsp90α. Here, we demonstrated that the lack of Hsp90α in HT1080 cells leads to an up-regulation of the constitutively expressed Hsp90β and several important Hsp90 co-chaperones (Aha1, Hop, and others). The expression of the major chaperones of the Hsp70 machinery (Hsp70-1, Hsp70-2, Hsc70) was also significantly induced. The components of the prefoldin-chaperonin folding arm and PFDL, R2TP, and R2SP complexes, as well as the major mitochondrial chaperones, were also largely up-regulated in Hsp90α-KO cells, while the expression of ER-resident chaperones/co-chaperones was either repressed or did not change.
We demonstrated here for the first time an adaptation of the cell chaperone machinery to the loss of the Hsp90α chaperone, which may be important for understanding the molecular mechanisms of action of Hsp90α-specific inhibitors and elaborating new therapy strategies in combating cancer, including the combination of Hsp90α-targeted therapy.
Recently, we have shown that the knockout of the HSP90AA1 gene encoding Hsp90α in human fibrosarcoma HT1080 cells does not affect basic cellular processes in normal and stressful conditions, which suggests an adaptation of the cell chaperone machinery to the loss of Hsp90α. Here, we demonstrated that the lack of Hsp90α in HT1080 cells leads to an up-regulation of the constitutively expressed Hsp90β and several important Hsp90 co-chaperones (Aha1, Hop, and others). The expression of the major chaperones of the Hsp70 machinery (Hsp70-1, Hsp70-2, Hsc70) was also significantly induced. The components of the prefoldin-chaperonin folding arm and PFDL, R2TP, and R2SP complexes, as well as the major mitochondrial chaperones, were also largely up-regulated in Hsp90α-KO cells, while the expression of ER-resident chaperones/co-chaperones was either repressed or did not change.
We demonstrated here for the first time an adaptation of the cell chaperone machinery to the loss of the Hsp90α chaperone, which may be important for understanding the molecular mechanisms of action of Hsp90α-specific inhibitors and elaborating new therapy strategies in combating cancer, including the combination of Hsp90α-targeted therapy.
Authors
Petrenko Petrenko, Vrublevskaya Vrublevskaya, Skarga Skarga, Zhmurina Zhmurina, Morenkov Morenkov
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