The Hsp70 family of molecular chaperones is essential for
protein folding, re-folding misfolded client proteins, clearance
of aberrant client proteins, and can also inhibit programmed
cell death. There are two major cytosolic members of this
family: the constitutive Hsc70, and the inducible Hsp72. Under
stress conditions the Hsp70 family protects the cell from
protein related damage by the induction of Hsp72. Hsc70 and
Hsp72 are highly homologous with minor differences in
substrate binding. In cancers, Hsp72 is commonly induced and
this induction is thought to aid in cancer cell survival. In these
studies we demonstrate the differential regulation of the prosurvival
kinase Akt by Hsc70 and Hsp72. We demonstrate that
of the two cytosolic forms, Hsp72 is the primary Akt regulator.
Using a phenothiazine class inhibitor of Hsp70-family activity,
methylene blue, we demonstrate dose dependent decreases in
the levels of Akt; produced breast cancer specific cell death.
This cell death could be rescued by the use of an Hsp70 family ATPase stimulating compound, SW02. We also demonstrate a
similar phenotype with a rhodacyanine class Hsp70 family
inhibitor, YM-1, also capable of reducing Akt and causing
cancer specific cytotoxicity. The resulting Akt decreases were
sufficient to block a tamoxifen-resistance pathway, allowing
previously resistant cells to regain sensitivity to tamoxifen.
These results demonstrate the capabilities of Hsp70 family
inhibitors as potent compounds for the treatment of breast
cancer.
| Identifer | oai:union.ndltd.org:USF/oai:scholarcommons.usf.edu:etd-5301 |
| Date | 01 January 2012 |
| Creators | Koren, John |
| Publisher | Scholar Commons |
| Source Sets | University of South Flordia |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Graduate Theses and Dissertations |
| Rights | default |
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