Graduation Year

2012

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Medical Sciences

Major Professor

Chad A. Dickey

Keywords

Breast Cancer Signaling Pathways, Hsp70 Inhibitors, Molecular Chaperones, Stress Response, Tamoxifen Resistance

Abstract

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.

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