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Date Available

7-26-2018

Year of Publication

2016

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Medicine

Department/School/Program

Toxicology and Cancer Biology

Faculty

Dr. Vivek Rangnekar

Faculty

Dr. Isabel Mellon

Abstract

Most primary tumors are heterogeneous and are often composed of therapy-sensitive and emerging therapy-resistant cancer cells. Rather unexpectedly, treatment of therapy-sensitive tumor cells in heterogeneous tumor microenvironments resulted in apoptosis of the therapy-resistant cancer cells. We identified a novel Par-4 amino-terminal fragment (PAF, which includes amino acids 1-131 of Par-4) that is produced and released by therapy-sensitive cancer cells following therapy-induced caspase-dependent cleavage of the tumor suppressor Par-4. PAF caused paracrine apoptosis in therapy-resistant cancer cells. Unlike Par-4-inducible apoptosis, which is dependent on the cell surface GRP78 receptor, PAF produced cancer-selective apoptosis independent of cell surface GRP78 function. Par-4 contains a VASA segment at amino acids 68-73 that is involved in binding and degradation of Par-4 by ubiquitin ligases, resulting in the loss of its pro-apoptotic function. On the other hand, this VASA segment in PAF translocates selectively into cancer cells, binds to the ubiquitin ligase FBXO45, and releases FBXO45 bound Par-4 for cancer cell-specific apoptosis via activation of the FADD/caspase 8/caspase 3 pathway. Collectively, our findings identify a novel mechanism by which cancer therapeutics utilize tumor heterogeneity to overcome resistance in cancer cells.

Digital Object Identifier (DOI)

http://dx.doi.org/10.13023/ETD.2016.306

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