Abstract
Prostate cancer is a clinically heterogeneous disease, ranging from indolent asymptomatic disease to very aggressive metastatic and life threatening forms of the disease. Distant metastasis represents the major lethal cause of prostate cancer. The most critical clinical challenge in the management of the patients is identifying those individuals at risk of developing metastatic disease. To understand the molecular mechanisms of prostate cancer metastasis and identify markers with metastatic potential, we have analyzed protein expression in two syngeneic prostate cancer cells lines PC3-N2 and PC3-ML2 using isobaric tags for relative and absolute quantitation labeling and multi-dimensional protein identification technology liquid chromatography matrix assisted laser desorption ionization tandem mass spectrometry. PC3-N2 is lowly metastatic while PC3-ML2 highly metastatic. A total of 1,756 proteins were identified in the analyses with 130 proteins showing different expression levels (p<0.01) in the two cell lines. Out of these, 68 proteins were found to be significantly up-regulated while 62 are significantly down-regulated in PC3-ML2 cells compared with PC3-N2 cells. The upregulation of plectin and vimentin which were the most significantly differentially expressed were validated by Western blot and their functional relevance with respect to invasion and migration was determined by siRNA gene silencing. To our knowledge, this study is the first to demonstrate that up-regulation of vimentin and plectin expression positively correlates with the invasion and metastasis of androgen-independent PCA.
Highlights
In Europe and the US, Prostate cancer (PCa) is the most prevalent cancer among men and the third most common cause of cancer related-deaths
We conclude that a reduction in the levels of both plectin and vimentin produced by the cells resulted in suppressed cell invasion in the prostate cancer cell line. These results demonstrate that knockdown of plectin and vimentin decreases the motility of PC3 cell lines supporting previous reports that downregulation of these proteins is involved in invasion and migration important initial steps in cancer metastasis
We have determined the global expression of proteins in syngeneic prostate cancer cell lines with different metastatic potentials to determine their potential roles in metastasis using isobaric Tags for Relative and Absolute Quantitation’ (iTRAQ) labeling and MUDPIT-LC-MALDI-MS/MS
Summary
In Europe and the US, Prostate cancer (PCa) is the most prevalent cancer among men and the third most common cause of cancer related-deaths. The identification of prostate biopsy or serum based biomarker(s) for predicting the susceptibility of men to develop metastasis will potentially better discriminate the more aggressive metastatic forms of the disease and provide better treatment and clinical management opportunities for the disease. The U.S Preventive Services Task Force (USPSTF) recommended against PSA-based screening for PCa in all age groups stating that the benefits do not outweigh the harms of screening and treatment [11] This inability to accurately predict the aggressiveness of prostate cancer based solely on standard clinicopathologic features clearly underscores the need to explore the ability of tumor-based biomarkers to enhance outcome prediction at biopsy and to understand the molecular basis of prostate cancer metastasis. The differentially regulated proteins identified in the study, including plectin and vimentin, are discussed in the context of their significance to prostate cancer progression
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