Gelsolin suppresses tumorigenicity through inhibiting PKC activation in a human lung cancer cell line, PC10

Abstract

Gelsolin expression is frequently downregulated in lung cancer and several types of different human cancers. To examine the effects of gelsolin restoration on tumorigenicity, we here stably expressed various levels of gelsolin via gene transfer in lung cancer cells (squamous cell carcinoma line, PC10). We observed the alterations in tumorigenicity in vivo when implanted in nude mice, and the changes in growth properties in vitro. As compared to parental cells and control clones, gelsolin transfectants highly reduced tumorigenicity and repressed cell proliferation. Moreover, we investigated bradykinin-induced responses in gelsolin-overexpressing clones, because agonist-stimulated activation of the phospholipases C (PLC)/protein kinase C (PKC) signal transduction pathway is critical for cell growth and tumorigenicity. Bradykinin promotes phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis by PLC and translocation of various PKC isoforms from the cytosolic fraction to the particulate fraction. Bradykinin treatment did not increase inositoltriphosphate (IP3) production and induce the membrane fractions of PKCa and PKCg in gelsolin tranfectants, while it induced PIP2 hydrolysis and increased the fractions in parental and control clones. These results suggest that gelsolin suppressed the activation of PKCs involved in phospholipid signalling pathways, inhibiting cell proliferation and tumorigenicity.

Aldehyde dehydrogenase 1A1 and gelsolin identified as novel invasion-modulating factors in conditioned medium of pancreatic cancer cells

“…Our results suggest that the invasion-inhibitory effects of CM#8 may be in part due to GSN expression. GSN expression suppresses the activation of phospholipase C (PLC)/protein kinase C (PKCs) involved in phospholipid signalling pathways, thus inhibiting cell proliferation and tumourigenicity [31]. Furthermore, Tanaka et al [32] functionally knocked down GSN expression by siRNA in the human mammary epithelial cell line, MCF10A, and suggested that GSN functions as a switch that controls E-and N-cadherin conversion via the transcription factor Snail.…”

Gene expression profiling of colon cancer by DNA microarrays and correlation with histoclinical parameters

“…Among the downregulated genes in cancer samples were genes encoding cytokines (IL10RA, IL1RN, IL2RB) , proteins involved in lipid metabolism (LPP, LIAS, LRP2, MGLL) (BirkenkampDemtroder et al, 2002), signal transducers (PLCD1, PLCG2, mTOR/FRAP1) , transcription factors such as RELA, and other known or putative tumour suppressor genes (TSG) such as CTCF that encodes a transcriptional repressor of MYC and is located in 16q22.1, chromosomal region frequently deleted in human tumours (Filippova et al, 1998) and IRF1, a transcriptional activator of genes induced by cytokines and growth factors, which regulates apoptosis and cell proliferation and is frequently deficient in human cancers (Tamura et al, 1996). The downregulation of GSN (gelsolin), combined with that of PRKCB1, may concur to decrease the activation of PKCs involved in phospholipid signalling pathways and inhibit cell proliferation and tumorigenicity (Sagawa et al, 2003).…”

Gelsolin gene silencing involving unusual hypersensitivities to dimethylsulfate and KMnO4in vivo footprinting on its promoter region

“…[3][4][5][6][7] These findings were also demonstrated in breast and prostate cancers. 8,9 On the other hand, a subset of non small cell lung cancers is characterized by high expression levels of gelsolin correlated with lymphatic invasion, 10 and there was a gradual increase in gelsolin with an increase in tumor grade and stage in uroepithelial carcinoma.…”

“…1,2 Previously, we reported that the expression of gelsolin, an actin-regulatory protein, is frequently silenced in various cancers, including stomach, colon, urinary bladder and lung, and that gelsolin functions as a tumor suppressor. [3][4][5][6][7] These findings were also demonstrated in breast and prostate cancers. 8,9 On the other hand, a subset of non small cell lung cancers is characterized by high expression levels of gelsolin correlated with lymphatic invasion, 10 and there was a gradual increase in gelsolin with an increase in tumor grade and stage in uroepithelial carcinoma.…”