Abstract B49: LaminA/C protein is overexpressed in tissue-invading prostate cancer and promotes prostate cancer cell growth, migration, and invasion through the PI3K/AKT/PTEN pathway

Abstract

Abstract Objectives: Prostate cancer (PCa) is a very heterogeneous tumor and only PCa with a high potential for progression and metastasis require aggressive treatment. This demands for new markers for these tumor properties. A previous proteomics study suggested the nuclear membrane proteins laminA/C to be a maker discriminating low and high Gleason score tumors and identifying high risk cancers. In addition, in-vitro data suggest a role of progerin, a truncated form of Lamin A in tumorigenesis. To characterize the function of laminA/C in prostate cancer cells, we performed a detailed expression analysis in prostate cancer tissue and explored the consequences of down or up-regulation of laminA/C in prostate cancer cells. Methods: The LaminA/C expression pattern in malignant and nonmalignant prostate tissue was investigated by immunohistochemistry (IHC). For statistical analysis of expression a tissue microarray (TMA) of 94 prostate cancer cases was used. For functional analysis LaminaA/C was overexpressed using cDNA overexpression vectors or knock-down by shRNA, respectively, in LNCaP, DU-145, and PC-3 prostate cancer cells. Subsequently, effects on proliferation (cell viability assay) migration (wound healing and migration through a porous membrane), invasion through a layer of extracellular matrix and activation of the phosphoinositide 3-kinase (PI3K)/AKT/PTEN survival pathway were assessed using western blot. Results: Our results confirm an increased laminA protein expression in high Gleason score cancers. The expression pattern indicated an association with high risk cancers. Lamin A protein levels were found increased in cell formations at the invasion fronts of tumors and in invasion “spearheading” tumor cell clusters. In the prostate tumor cell lines LNCaP, DU-145, and PC-3 knockdown or overexpression of laminA/C resulted in inhibition or stimulation, respectively, of cell growth, colony formation, migration and invasion. Further mechanism studies suggested that the laminA/C-related malignant behavior is regulated through modulation of the phosphoinositide 3-kinase (PI3K)/AKT/PTEN signaling pathway. Western blot results indicated that knockdown or overexpression of laminA/C decreased or increased, respectively, protein levels of the PI3K subunits p110 and p85 in all 3 cell lines; phosphor-AKT in the PTEN negative cell lines LNCaP and PC-3, and, increased or decreased, respectively, PTEN protein levels in PTEN positive Du-145 cells. Conclusion: Together, our data suggest that laminA/C proteins are positively involved in malignant behavior of prostate cancer cells through the PI3K/AKT/PTEN pathway. Differential expression of Lamin A/C in benign tissue, lower and higher GS tumors with association to infiltrating and invading cancer cell formations suggest a role as an invasion and progression factor. LaminA/C may represent a new oncogenic factor and a novel therapeutic target for prostate cancer. Citation Format: Lu Kong, Georg Schaefer, Huajie Bu, Yong Zhang, Yuxiang Zhang, Helmut Klocker. LaminA/C protein is overexpressed in tissue-invading prostate cancer and promotes prostate cancer cell growth, migration, and invasion through the PI3K/AKT/PTEN pathway [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B49.