PKD1 negatively regulates cell invasion, migration and proliferation ability of human osteosarcoma

Abstract

Abstract. Osteosarcoma (OS) is a primary malignancy of the bone, with a tendency to metastasize early. Despite intensive chemotherapy and surgical resection, more than 30% of patients develop distant metastases, and the prognosis of patients with metastases is essentially poor. Members of the protein kinase D (PKD) family are serine/threonine kinases, and have been studied in various cancers. Among the three different isoforms of this family, PKD1 is one of the best understood for its role in human malignancies; however, its role in musculoskeletal tumors has not been studied. In the present study, we investigated the role of PKD1 in human OS. We first analyzed PKD1 mRNA expression in human musculoskeletal tumor tissue samples by quantitative real-time PCR. PKD1 expression in OS samples was significantly lower than that in benign schwannoma samples, and this was correlated with metastatic potential. In in vitro studies, overexpression of PKD1 by plasmid transfection decreased OS cell invasion, migration and proliferation, and significantly decreased matrix metalloproteinase (MMP)2 mRNA expression. Conversely, siRNA knockdown of PKD1 increased invasion, migration and proliferation of OS cells, and MMP2 expression was markedly increased. Furthermore, overexpression of PKD1 significantly reduced in vivo tumor growth of OS cells. These results demonstrated that low expression of PKD1 may contribute to increased cell invasion, migration and proliferation ability of human OS. Taken together, our findings strongly suggest that PKD1 may negatively regulate the malignant potential of human OS, and may be a therapeutic target for human OS in the clinical setting.

Protein kinase D2 contributes to TNF-α-induced epithelial mesenchymal transition and invasionviathe PI3K/GSK-3β/β-catenin pathway in hepatocellular carcinoma

“…The expression patterns and effects of PKD isoforms differ among various types of cancer. PKD1 is reported to play an inhibitory role in cell migration and invasion of several malignancy [ 27 - 30 ]. PKD2 and PKD3 are overexpressed in some highly invasive cancer cells and are demonstrated to accelerate cancer cell invasion through the AKT, ERK and NF-κB signaling pathways [ 4 , 14 , 26 , 31 ].…”

Pharmacologic reversion of epigenetic silencing of the PRKD1promoter blocks breast tumor cell invasion and metastasis

“…Moreover, loss of PKD1 has been associated with increased invasiveness and risk of metastases in gastric cancer and osteosarcoma [39,40]. We previously have shown the importance of PKD1 for breast cancer cell invasion by demonstrating that a knockdown of PKD1 in the low invasive breast cancer cell line MCF-7 led to an increase of its invasive potential, and reexpression of a constitutively active PKD1 in highly invasive MDA-MB-231 cells impaired their invasive phenotype [12].…”

Protein Kinase D Isoforms Differentially Modulate Cofilin-Driven Directed Cell Migration

“…The relative contributions of different endogenous PKD isoforms to both signaling pathways have not been fully elucidated. Puzzling in the PKD literature is that different isoforms, or even the same isoform, have been attributed pro- or anti-migratory functions [12], [14], [17], [18], [19], [20], [21], [22], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44]. For example, for PKD3 it was shown that chemical inhibition [22], but also overexpression of active PKD3 blocked directed cell migration [19].…”