p53 and NGAL: dual regulatory roles in advanced prostate cancer

Abstract

The development of prostate cancer from small regions of hyperplasia to invasive tumors requires genetic and epigenetic alterations of critical cellular components to aid in the development of cells more adapted for aberrant growth. Cell cycle control by the transcription factor p53 is necessary for the homeostatic proliferation and death of cells in response to DNA damage. Examination of prostate cancer cell lines harboring either wild-type (22Rv-1, LNCaP) or non-functional mutated p53 protein (DU145, PC3) responses to commonly used chemotherapeutic drugs demonstrated that p53 protein status dictated the apoptotic effectiveness a given drug would have on prostate cancer treatment. Moreover, restoration of functional p53 in p53-negative DU145 cells activated the Raf/MEK/ERK pathway through increased expression of a receptor tyrosine kinase, DDR1. Expression of NGAL, a small secreted extracellular protein belonging to the lipocalin super family, in early androgen receptor (AR) positive prostate cancer cell lines (22Rv-1, LNCaP) was demonstrated to increase these cells' invasiveness by their enhanced abilities to form colonies in soft agar. Conversely, reduced expression of NGAL in advanced AR negative prostate cancer cell lines (DU145, PC3) by use of a NGAL specific shRNA vector decreased their soft agar colony formation ability. In contrast to previously published studies, NGAL expression does not appear to augment drug sensitivity in these cell lines suggesting that NGAL's function in cancer is cell type specific. We also report here that the regulation of NGAL was mediated, in part, by NF-κB as a direct transcriptional target as previously reported and by p53 through some as of yet unknown mechanism. Detection of NGAL and NGAL:MMP-9 complexes in the urine of prostate patients, as well as others (glioblastoma, head & neck), indicated that NGAL could be potentially used as a biomarker for disease presence and progression. Taken together, our data suggests that p53 and NGAL function in the development and progression of prostate cancer.