Lamin A/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

Prostate cancer (PC) remains the second most common cause of cancer-related death in Western countries. A previous proteomics study suggested that the nuclear membrane protein lamin A/C to be a maker to discriminate low- and high-Gleason score tumors and to identify high-risk cancers. To characterize its function in PC cells, we performed a detailed expression analysis in PC tissue and explored the consequences of down or upregulation of lamin A/C in PC cells. Our results confirm an increased lamin A/C protein expression in high-risk cancers and show association of expression with tumor cell formations at the invasion fronts of tumors and in invasion 'spearheading' tumor cell clusters. In the prostate tumor cell lines, LNCaP, DU145, and PC3 small hairpin RNA knockdown or overexpression of lamin A/C resulted in inhibition or stimulation, respectively, of cell growth, colony formation, migration and invasion. Further mechanism studies suggested that the lamin A/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 lamin A/C decreased or increased, respectively, protein levels of the PI3K subunits p110 and p85 in all three cell lines; phosphor-AKT in the PTEN-negative cell lines LNCaP and PC3, and, increased or decreased, respectively, PTEN protein levels in PTEN-positive DU145 cells. Together, our data suggest that lamin A/C proteins are positively involved in malignant behavior of PC cells through the PI3K/AKT/PTEN pathway. Lamin A/C may represent a new oncogenic factor and a novel therapeutic target for PC.

Two-dimensional gel electrophoresis analysis of the leiomyoma interstitial fluid reveals altered protein expression with a possible involvement in pathogenesis

“…lamins constitute a class of intermediate filaments with structural and functional roles, closely associated with the inner nuclear membrane, nuclear pore complexes and chromatine (36). A decreased expression of lamin A/C in low-grade cancer compared with benign epithelium was observed (37). Results of those studies are in agreement with our findings for the leiomyoma and normal myometrium.…”

“…Results of those studies are in agreement with our findings for the leiomyoma and normal myometrium. This protein may have a role in the regulation of cell proliferation (37).…”

The clinicopathological significance of lamin A/C, lamin B1 and lamin B receptor mRNA expression in human breast cancer

“…Lamin A/C overexpression has been implicated in human prostate cancer. It is believed to effect cell motility and growth via the PI3K/AKT/PTEN pathway [10]. Defects in nuclear lobulations are well documented in human prostate cancer cell lines, which are described as lamin B deficient micro-domains (LMDM).…”

“…Mutations in the LMNA gene cause a spectrum of degenerative disorders ranging from muscular dystrophies to premature ageing known as the laminopathies [4,[7][8][9]. A-type lamins have been implicated in prostate, colon and gastric carcinogenesis, while B-type lamins have been suggested to have roles in prostate cancer and hepatocarcinoma [10][11][12]. In this study, we have endeavored to elucidate the relationships between the mRNA expressions of A-type lamins and LMNB1 and LBR genes and the clinicopathological parameters of human breast cancer.…”

The Role of the Nuclear Lamina in Cancer and Apoptosis

“…Even in normal cells, overexpression of normal lamin A leads to increased senescence and apoptosis [ 71 ]. In cancer, the impact of lamin overexpression may be different since a recent study showed that in prostate cancer cells, transfection of A-type lamins leading to overexpression causes enhanced growth, invasion, and migration by activation of the PI3K/AKT/PTEN pathway [ 72 ], while knockdown of lamins in the same cell culture has opposite effects. On the other hand, knockdown of lamin B1 leads to apoptosis rather than necrosis after induction of cell death in the mouse mammary tumor FM3A cell line [ 73 ].…”