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Ryder Dissertation 2013 4-4.pdf (1.42 MB)

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THE EFFECTS OF ACIDOSIS ON SURVIVAL PATHWAYS IN LYMPHOID MALIGNANCIES

Ryder, Christopher Brown
http://rave.ohiolink.edu/etdc/view?acc_num=case1365180698

Abstract Details

2013, Doctor of Philosophy, Case Western Reserve University, Pharmacology.
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.
Clark Distelhorst (Advisor)
Paul MacDonald (Committee Chair)
George Dubyak (Committee Member)
Michael Maguire (Committee Member)
William Schiemann (Committee Member)
184 p.
Biomedical Research; Oncology; Pharmacology
Acidosis; Apoptosis; Cancer; Bcl-2; Bcl-2 family; TDAG8; GPR65; PUMA; Bim; Bcl-xL; CHOP; c-Jun

Recommended Citations

Citations

  • Ryder, C. B. (2013). THE EFFECTS OF ACIDOSIS ON SURVIVAL PATHWAYS IN LYMPHOID MALIGNANCIES [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1365180698

    APA Style (7th edition)

  • Ryder, Christopher. THE EFFECTS OF ACIDOSIS ON SURVIVAL PATHWAYS IN LYMPHOID MALIGNANCIES. 2013. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1365180698.

    MLA Style (8th edition)

  • Ryder, Christopher. "THE EFFECTS OF ACIDOSIS ON SURVIVAL PATHWAYS IN LYMPHOID MALIGNANCIES." Doctoral dissertation, Case Western Reserve University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1365180698

    Chicago Manual of Style (17th edition)

case1365180698
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© 2012, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.