PhD Dissertation Defense by Catera Wilder

Event Details
  • Date/Time:
    • Monday February 22, 2016
      8:00 am - 10:00 am
  • Location: Engineered Biosystems Building (EBB), Children's Healthcare of Atlanta Seminar Room
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Summaries

Summary Sentence: Mechanisms during cathepsin inhibition and their effects on substrate degradation and breast cancer cell invasion

Full Summary: No summary paragraph submitted.

Advisor:

Manu Platt, PhD (Georgia Institute of Technology)

Committee Members:

Melissa Kemp, PhD (Georgia Institute of Technology)

Valerie Odero-Marah, PhD (Clark Atlanta University)

Shelly Peyton, PhD (University of Massachusetts-Amherst)

Johnna Temenoff, PhD (Georgia Institute of Technology)

Title:

Mechanisms during cathepsin inhibition and their effects on substrate degradation and breast cancer cell invasion 

Abstract:

Currently, one out of every eight women in the U.S. will be diagnosed with breast cancer in their lifetime. Cysteine cathepsin proteases are powerful collagenases and elastases that play an important role in matrix remodeling and are upregulated in various diseases such as atherosclerosis, osteoporosis, and cancer. During cancer progression, tumor cells upregulate cysteine cathepsins to assist with the invasion and metastasis of the tumor. This has motivated pharmaceutical companies to develop protease inhibitors, but many have failed clinical trials due to adverse side effects. Currently there is limited research investigating cellular feedback mechanisms caused by cathepsin inhibitors. This highlights a need to understand how cathepsin inhibition affects cathepsin production. The objective of this work is to elucidate cellular feedback regulations of cysteine cathepsins during broad spectrum inhibition and possible mechanisms in order to develop more effective cathepsin inhibitors for breast cancer therapies.

 

This was accomplished by developing tools to selectively distinguish active cathepsins K, L, S, and V to appropriately quantify their levels in cells and tissue. Next, the inhibitor-induced effects on cathepsin activity with chemical or protein inhibitors in breast cancer cells was determined. Mechanisms by which inhibition of cathepsin activity induced active cathepsins were elucidated, and finally, the role in substrate degradation and cell invasion was investigated. The results of this work provide tools to selectively distinguish cathepsins by taking advantage of pH and substrate regulation and identifies a feedback response that elevates active cathepsins in response to cathepsin inhibition. These findings also demonstrate an interaction that occurs between two cathepsins within the cathepsin proteolytic network. Currently, there are limited studies investigating the effects of cathepsin inhibition on the cellular regulation of cathepsin amounts. Not only are these findings important for providing more effective treatment options for breast cancer, but this work has broad implications since cathepsins have been implicated in diseases such as HIV, atherosclerosis, and osteoporosis.

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PhD Dissertation Defense
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  • Created By: Jacquelyn Strickland
  • Workflow Status: Published
  • Created On: Feb 10, 2016 - 10:52am
  • Last Updated: Oct 7, 2016 - 10:16pm