Suppression of Prostate Tumor Growth and Metastasis by Inhibition of Vimentin

  • Watt, David (PI)

Grants and Contracts Details


Advanced prostate tumors that often metastasize to the lung, bone, and other vital tissues, are resistant to conventional therapy. Prostate apoptosis response-4 (Par-4) is a tumor suppressor that causes apoptosis in therapy-resistant prostate cancer cells. Although baseline levels of Par-4 secreted by cells are inadequate to induce apoptosis, normal cells can be induced to produce robust secretion of Par-4 protein that targets cancer cells in a paracrine manner. Accordingly, secreted Par-4 is systemically available in vivo and binds to its cell surface receptor GRP78 in cancer cells to trigger apoptosis in primary and metastatic tumors. Importantly, secreted Par-4 induces cancer-specific apoptosis, but it does not induce apoptosis in normal cells as GRP78 is expressed only on the surface of cancer cells, not on normal cells. “Small-molecule” drugs that efficiently and selectively induce Par-4 secretion without killing the normal cells would, therefore, represent an important therapeutic advance. In preliminary studies, we synthesized and screened newly developed 3-arylquinolines as well as related quinolones and quinothiolones for the secretion of Par-4 protein from normal mouse and human fibroblast and epithelial cells. This screening led to the identification of 2-amino-7-(N,N-dimethylamino)-3-(2’-fluorophenyl)quinoline (called “Arylquin-1”) as a member of a new class of agents that trigger robust secretion of Par-4 from normal cells at nanomolar, non-toxic concentrations. As expected, Par-4 secreted from these normal cells induced paracrine apoptosis in diverse prostate and lung cancer cell cultures, but not in normal cell cultures. Using a biotinylated, biologically active version of Arylquin-1, we identified vimentin, a protein linked to motility, invasion, EMT and metastasis, as the molecular target of Arylquin-1 that in turn produces Par-4 secretion. In this study, we will determine the effect of Arylquin-1 on Par-4 secretion from normal cells and apoptosis in prostate cancer cell culture and in vivo, on tumor growth in prostate cancer models. Computational dynamics revealed that Arylquin-1 forms a stable interaction with a hydrophobic pocket on vimentin. We will, therefore, determine the domains of Par-4 and vimentin that bind to each other to elucidate the mechanism underlying inhibition of Par-4 secretion by vimentin and its release by Arylquin-1. Consistent with the interaction of Arylquin-1 with vimentin, our preliminary studies also indicated that Arylquin-1 inhibits motility and invasion in prostate cancer cells by an apoptosis-independent mechanism. We will, therefore, study whether Arylquin-1 inhibits motility, invasion and EMT in cell culture and metastasis in mouse models of prostate cancer via vimentin-dependent mechanisms. Developing agents that selectively promote Par-4 secretion from normal cells, induce apoptosis in cancer cells and halt metastatic processes in prostate cancer would be of extraordinary academic and therapeutic value.
Effective start/end date7/1/156/30/20


Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.