PC-1/PrLZ Contributes to Malignant Progression in Prostate Cancer

Abstract

PC-1/PrLZ gene overexpression has been identified to be associated with prostate cancer progression. Previous studies have revealed that PC-1 possesses transforming activity and confers malignant phenotypes to mouse NIH3T3 cells. However, the functional relevance of PC-1 expression changes during prostate cancer development and progression remains to be evaluated. In this study, gain-of-function and lossof-function analyses in LNCaP and C4-2 cells, respectively, were implemented. Experimental data showed that PC-1 expression was in positive correlation with prostate cancer cell growth and anchor-independent colony formation in vitro, as well as tumorigenicity in athymic BALB/c mice. Moreover, PC-1 expression was also found to promote androgen-independent progression and androgen antagonist Casodex resistance in prostate cancer cells. These results indicate that PC-1 contributes to androgen-independent progression and malignant phenotypes in prostate cancer cells. Furthermore, molecular evidence revealed that PC-1 expression stimulated Akt/protein kinase B signaling pathway, which has been implicated to play important roles in promoting androgen refractory progression in prostate cancer. Increased PC-1 levels in C4-2 cells may represent an adaptive response in prostate cancer, mediating androgen-independent growth and malignant progression. Inhibiting PC-1 expression may represent a novel therapeutic strategy to delay prostate cancer progression.

Nonredundant Functions for Tumor Protein D52-Like Proteins Support Specific Targeting of TPD52

“…Common phenotypes included smaller, rounder cells with reduced actin stress fibers, and we also noted significant positive correlations between in situ D52 or D53 and cyclin B1 expression (data not shown), as reported for endogenous D53 expression in MCF-7 cells, and exogenous D53 expression in MDA-MB-231-derived D53-H1 cells (32). Distinct phenotypes represented increased proliferation and anchorage-independent growth in D52-expressing cell lines only, in agreement with the findings of Lewis et al (28), where mouse D52 was expressed in 3T3 cells, and of previous studies where the D52 isoform PC-1/PrLZ was expressed in different cell types (26,29). A common limitation of the present and previous studies is the use of fibroblast cell lines, and analyses of D52 overexpression in a breast cell line such as MCF10A may be more informative in terms of the role of D52 role in breast cancer.…”

“…Proliferation genes are emerging as a common driving force in prognostic cancer gene signatures (44). As D52 positively regulates cell proliferation and anchorage-independent growth (26,28,29), the reduced survival associated with high D52 expression in breast cancer likely reflects this contributing to a more proliferative and aggressive cancer phenotype. The identification of nonredundant cancer-promoting properties for D52 also support the specific targeting of D52 expression in cancer, as do the results of recent mapping studies indicating narrow gene amplification peaks at 81 Mb, corresponding to the position of the D52 locus (2 -5).…”

Tumor protein D52 represents a negative regulator of ATM protein levels

“…19 TPD52 promotes proliferation, migration/invasion, and metastasis in different cell models, 17,20,21 whereas knockdown of TPD52 induced apoptosis in breast and prostate cancer cell lines. 17,22 The underlying mechanisms are not yet fully understood, apart from the regulation of Akt/protein kinase B and Stat3/Bcl-2 signaling pathways shown in prostate cancer cell lines.…”

“…17,22 The underlying mechanisms are not yet fully understood, apart from the regulation of Akt/protein kinase B and Stat3/Bcl-2 signaling pathways shown in prostate cancer cell lines. 21,22 Studies have recently indicated a possible role of TPD52 in regulating DDR, where TPD52 levels positively correlated with G 2 chromosomal radiosensitivity in lymphocytes from women with or at risk of hereditary breast cancer. 23 A genome-wide association study combined with radiation cytotoxicity assays using human lymphoblastoid cell lines again identified TPD52 levels to be positively associated with radiation sensitivity, and TPD52 knockdown in multiple tumor cell lines significantly de-sensitized these cell lines to radiation treatment.…”

Tumor protein D52 (isoform 3) contributes to prostate cancer cell growth via targeting nuclear factor-κB transactivation in LNCaP cells

“…[15][16][17] Recent studies have demonstrated that TPD52 promotes metastasis; its expression increases with advancement of cancer and regulates apoptosis of cancer cells. 18,19 There was ample of interest given to TPD52 as an oncogene, due to its multifaceted functions in various cellular mechanisms and multiple carcinomas. 20,21 It is also proved that TPD52 increases lipid metabolism by facilitating de novo synthesis, exogenous uptake, and intracellular lipid storage.…”