Presentation Type

Poster

Title of Abstract

Hsp70 Inhibition Reduces Akt and Selectively Kills Breast Cancer Cells

Abstract

The family of 70-kDa proteins are molecular chaperones responsible for the noncovalent folding of many client proteins. including Akt,. Akt is a kinase client which is responsible for multiple anti-apoptotic and proliferation pathways. These oncogenic properties can be controlled by manipulating Hsp70 ATPase activity. By utilizing Hsp70 ATPase inhibitors we can reduce Akt levels in an Hsp70 dependent manner. These Akt reductions, coupled with the inhibition of the Hsp70 family of chaperones, yield cytotoxic events selective to cancer cells, specifically breast cancer. Here, we characterize two classes of Hsp70 family inhibitors, one a phenothiazine compound, methylene blue, as well as a novel rhodacyanine dye Ym1. Characterizations were conducted on the ER-positive breast cancer cell model MCF-7 cells, with functional readouts being LDH assays for toxicity, intracellular protein levels (Akt, ERa, etc.), as well as cellular localization. The goal of these experiments is to compare the effectiveness of these two Hsp70 inhibiting compounds. We aim to elucidate these two chemical backbones as potential targets for creating new compounds with both higher efficacy and specificity. The knowledge gained from understanding the biochemical properties of Hsp70 will demonstrate the viability of Hsp70 as a target in the treatment of cancer.

Categories

Biomedical Sciences

Research Type

Research Assistant

Mentor Information

Dr. Chad Dickey

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Hsp70 Inhibition Reduces Akt and Selectively Kills Breast Cancer Cells

The family of 70-kDa proteins are molecular chaperones responsible for the noncovalent folding of many client proteins. including Akt,. Akt is a kinase client which is responsible for multiple anti-apoptotic and proliferation pathways. These oncogenic properties can be controlled by manipulating Hsp70 ATPase activity. By utilizing Hsp70 ATPase inhibitors we can reduce Akt levels in an Hsp70 dependent manner. These Akt reductions, coupled with the inhibition of the Hsp70 family of chaperones, yield cytotoxic events selective to cancer cells, specifically breast cancer. Here, we characterize two classes of Hsp70 family inhibitors, one a phenothiazine compound, methylene blue, as well as a novel rhodacyanine dye Ym1. Characterizations were conducted on the ER-positive breast cancer cell model MCF-7 cells, with functional readouts being LDH assays for toxicity, intracellular protein levels (Akt, ERa, etc.), as well as cellular localization. The goal of these experiments is to compare the effectiveness of these two Hsp70 inhibiting compounds. We aim to elucidate these two chemical backbones as potential targets for creating new compounds with both higher efficacy and specificity. The knowledge gained from understanding the biochemical properties of Hsp70 will demonstrate the viability of Hsp70 as a target in the treatment of cancer.