THE EFFECTS OF ACIDOSIS ON SURVIVAL PATHWAYS IN LYMPHOID MALIGNANCIES

Intensive research in the field has revealed that, within tumors, cancer cells must grow and develop amidst an increasingly complex and demanding background. Cancer cells acquire the ability to recognize and respond to numerous features of this tumor microenvironment, generating a cellular-environmental crosstalk that shapes the cancer phenotype. In this work we sought a better understanding of the mechanisms by which cancer cells respond to one such physical hallmark of the tumor microenvironment, extracellular acidosis. Importantly, tumor acidity correlates with aggressive phenotypes and resistance to therapy. Yet, the basis for these observations remains poorly understood. Herein we report that acidosis promotes the inappropriate survival of cancer cells through regulation of several apoptosis-governing members of the Bcl-2 family. More specifically, we find that acidosis signals the elevation of anti-apoptotic Bcl-2 and Bcl-xL, while also reducing levels of pro-apoptotic PUMA and Bim. Further mechanistic studies revealed that the induction of anti-apoptotic Bcl-2 proteins occurs in response to activation of the acid-sensing G protein-coupled receptor GPR65, an oncogene found to be expressed in a number of human cancers. Additional studies on the regulation of pro-apoptotic Bcl-2 family members led to the discovery that acidosis blocks a pro-apoptotic function of c-Jun to elevate PUMA expression. This multi-faceted regulation of Bcl-2 proteins, which play a critical role in cancer cell survival decisions, explains the tumor promoting function of acidosis and offers rationale for targeting both GPR65 and Bcl-2 proteins in the acidic tumor microenvironment.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Pharmacology

Grantor dc:publisher

Case Western Reserve University School of Graduate Studies

Year dc:date

2013

Author dc:creator

• Ryder, Christopher Brown

Contributors dc:contributor

• Distelhorst, Clark
• MacDonald, Paul

• Biomedical Research
• Oncology
• Pharmacology
• Acidosis
• Apoptosis
• Cancer
• Bcl-2
• Bcl-2 family
• TDAG8
• GPR65
• PUMA
• Bim
• Bcl-xL
• CHOP
• c-Jun

Statement dc:rights

• unrestricted
• This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

Language dc:language

English

Repository record dc:identifier

http://rave.ohiolink.edu/etdc/view?acc_num=case1365180698

OAI identifier oai:identifier

oai:etd.ohiolink.edu:case1365180698