Year of Publication

2016

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department

Toxicology and Cancer Biology

First Advisor

Dr. Vivek Rangnekar

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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