Investigating The Roles Of P63 And P73 Isoforms To Therapeutically Treat P53-Altered Cancers

Author

Avinashnarayan Venkatanarayan, The University of Texas Graduate School of Biomedical Sciences at HoustonFollow

Date of Graduation

5-2015

Document Type

Dissertation (PhD)

Program Affiliation

Genes and Development

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Dr. Elsa R. Flores

Committee Member

Dr. Mong Hong Lee

Committee Member

Dr. Michael J. Galko

Committee Member

Dr. Kenneth Y. Tsai

Committee Member

Dr. Sendurai Mani

Committee Member

Dr. Preethi Gunaratne

Abstract

Investigating the roles of p63 & p73 isoforms to therapeutically treat

p53-altered cancers

Avinashnarayan Venkatanarayan, M.S.

Supervisory Professor: Elsa R. Flores, Ph.D.

The TP53 tumor suppressor is mutated in approximately 50% of human cancers rendering cancer therapies ineffective. p53 reactivation suppresses tumor formation in mice. However, this strategy has proven difficult to implement therapeutically. An alternate approach to overcome p53 loss is to manipulate the p53-family members, p63 and p73, which interact and share structural similarities to p53. p63 and p73, unlike p53 are less frequently mutated and have two major isoforms with distinct functions which makes them unique targets for therapeutic intervention. The full-length acidic transactivation (TA) isoforms of p63 and p73 function similar to p53. While the deltaN (ΔN) isoforms of p63 and p73, which lack the acidic transactivation domain, are overexpressed in cancers and function in a dominant negative manner against p53, TAp63 and TAp73. As result of the opposing isoform-specific function, the roles of p63 and p73 in tumorigenesis requires further characterization. In an attempt to identify novel therapeutic approaches to treat p53-altered cancers by utilizing the p53-family members, I aim to delineate the roles of ΔN isoforms of p63 and p73 in tumorigenesis.

I have demonstrated that deletion of ΔNp63 or ΔNp73 in p53-deficient tumors mediates tumor regression through the upregulation of tumor suppressive isoforms, TAp63 and TAp73. Upon loss of ΔNp63 or ΔNp73, TAp63 and TAp73 activate IAPP a metabolic regulator, which induces metabolic reprogramming resulting in tumor regression in p53-deficient mice. I have shown that IAPP, which encodes amylin, a 37-amino acid peptide functions as a tumor suppressor in p53-deficient cancers. IAPP functions through the calcitonin and RAMP3 receptors to limit glucose uptake and reduce glycolysis in the cancer cells resulting in ROS accumulation and apoptosis. Additionally, I have also shown that use of Pramlintide, a synthetic analog of IAPP, mediates tumor regression in p53-deficient mice and apoptosis in multiple p53-mutant human cancer cell lines.

Further, to therapeutically treat p53-deficient cancers in vivo, liposomal nanoparticle siRNA’s targeting ΔNp63 and ΔNp73 were administered into p53-deficient mouse thymic lymphomas, which resulted in tumor regression. Taken together, my work has defined the isoform specific functions of p63 and p73 in tumorigenesis. Importantly, I have also demonstrated the use of pramlintide, a diabetic drug to treat p53-altered cancers. Thus, by understanding the interplay among the p53-family members, novel therapeutic methods could be designed to treat p53-altered human cancers.

Keywords

p53-superfamily, p63 & p73 isoforms and functions, cancer metabolism, Pramlintide therapy, Liposomal siRNA delivery, mouse models