GTMB 7 - Gene Therapy & Molecular Biology

Gene Therapy and Molecular Biology Vol 7, page 239Gene Ther Mol Biol Vol 7, 239-243, 2003.PRL-3 as a target for cancer therapyResearch ArticleKoh Vicki, Fu Jianlin, Guo Ke, Lip Kuo Ming, Li Jie and Zeng Qi*Institute of Molecular and Cell Biology, 30 Medical Drive, Singapore 117609, Singapore__________________________________________________________________________________*Correspondence: Zeng Qi, Ph.D., Institute of Molecular and Cell Biology, 30 Medical Drive, Singapore 117609, Singapore Tel: 65-6874-3752; Fax: 65-6779-1117; e-mail: mcbzengq@imcb.nus.edu.sgKey Words: PRL-1, -2 and -3, prenylated phosphatase, cancer metastatasis, phosphatase inhibitor, therapeutic target and cancer therapyAbbreviations: phosphatase of regenerating liver (PRL); protein tyrosine phosphatases (PTPs); Chinese Hamster Ovary (CHO) cells;cells; serial analysis of gene expression (SAGE) technology; human embryonic kidney fibroblasts HEK293; restriction enzyme mediatedintegration, (REMI)Received: 24 October 2003; Revised: 3 December 2003;Accepted: 4 December 2003; electronically published: December 2003SummaryA group of protein tyrosine phosphatases (PTPs), the PRL family, has been implicated in the contribution andprogression of cancer metastasis. The PRL family consists of three members: PRL-1, -2 and -3. This small (20kD)class of prenylated protein tyrosine phosphatase contains a PTP signature motif (VHCXAGXXR) at their activesites and a catalytic domain, similar to dual specificity phosphatases. The three closely related PRLs share 76-87%identities in their amino acid sequences, with a unique C-terminal prenylation motif and with significant sequencehomology to Cdc14p, a mitotic regulator, and PTEN/MMAC1, the tumor suppressor (Zeng et al, 1998a). PRL-1 wasidentified as an immediate-early gene which was induced in mitogen-stimulated cells and regenerating liver. PRL-3,along with PRL-2, was identified subsequently by using PRL-1 sequence to search mouse EST database. Recently,PRLs have been implicated in the process of oncogenic transformation and cancer metastasis. We suggest thatPRLs might be important modulators in the process of cancer metastasis and are therefore potential targets fortherapeutic intervention of cancer.I. IntroductionPRL proteins are conserved from human to C.elegans (Figure 1). We suggested that they have commoncritical physiological functions, but each might has its owndistinct target substrates. PRL-1 is expressed at high levelsin proliferating cells and a number of human tumor celllines, including HeLa (Diamond et al, 1994; Wang et al,2002). Overexpression of PRL-1 and PRL-2 in epithelialcells results in a transformed phenotype in culture andtumor growth in nude mice (Cates et al, 1996; Zeng et al,2003). By PCR-based subtractive hybridization, PRL-2was shown to be upregulated 1.8, 2.7 and 4-fold inadvanced prostate cancer cell lines LNCaP, PC-3 and DU-145 respectively, in comparison with normal epithelialcells. The data suggest that PRL-2 is associated withprostate tumor progression (Wang et al, 2001). Recently,by using serial analysis of gene expression (SAGE)technology, researchers (Bert Vogelstein and hiscolleagues) at the Johns Hopkins Medical Institutesreported that among 144 upregulated genes detected inmetastatic colorectal liver samples, PRL-3 was the onlygene specifically overexpressed in all 18 metastaticcolorectal cancers examined (Saha et al, 2001). We foundthat prenylated PRL-1 and -3 are enriched on the plasmamembrane (Zeng et al, 2000, 2003). Overexpression ofPRL-1 and -3 in Chinese Hamster Ovary (CHO) cellspromotes cell migration, invasion and metastasis.Moreover, PRL-1 and -3 overexpressing CHO cells arecapable of inducing metastatic tumor formation in nudemice (Zeng et al, 2003). Overexpression of PRL-3 inhuman embryonic kidney fibroblasts HEK293 cells hasalso been found to enhance growth rates versus nontransfectedcells (Matter et al, 2001). Taken together, thesedata suggest that the PRL-1, -2 and -3 might be associatedwith cancer metastasis and act as major players inoncogenic and metastatic processes. How does PRL-3 spurcolon cancer metastasis? How might PRLs be involved inthe pathways of signal transduction related to cancerdevelopment and metastasis? Much remains to be learnedfrom these striking discoveries to answers. Here, wesuggest that PRL-3 might serve as one of the importantmarkers to track the events leading to colon cancermetastasis. We speculate that an excess of PRLphosphatases activity could bring about key alterationsthat would contribute to the acquisition of metastaticproperties in tumor cells. PRLs may therefore be potentialtargets for new cancer therapeutic strategies.239