Abstract
High expression of 3-phosphoinositide-dependent protein kinase-1 (PDK1) has been detected in various invasive cancers. In the current study, we investigated its role in cancer cell migration and experimental metastasis. Down-regulation of PDK1 expression by small interference RNA markedly inhibited spontaneous migration and epidermal growth factor (EGF)-induced chemotaxis of human breast cancer cells. The defects were rescued by expressing wild-type PDK1. PDK1-depleted cells showed impaired EGF-induced actin polymerization and adhesion, probably due to a decrease in phosphorylation of LIM kinase/cofilin and integrin beta1. Confocal microscopy revealed that EGF induced cotranslocation of PDK1 with Akt and protein kinase Czeta (PKCzeta), regulators of LIM kinase, and integrin beta1. Furthermore, PDK1 depletion dampened EGF-induced phosphorylation and translocation of Akt and PKCzeta, suggesting that Akt and PKCzeta functioned downstream of PDK1 in the chemotactic signaling pathway. In severe combined immunodeficiency mice, PDK1-depleted human breast cancer cells formed more slowly growing tumors and were defective in extravasation to mouse lungs after i.v. injection. Our results indicate that PDK1 plays an important role in regulating the malignant behavior of breast cancer cells, including their motility, through activation of Akt and PKCzeta. Thus, PDK1, which increases its expression in cancer cells, can be used as a target for the development of novel therapies.
Highlights
Invasion and metastasis are the major causes of mortality and morbidity in cancer [1]
Our results revealed that PDK1 plays an important role in sustaining the malignant phenotype of human breast cancer cells
Our studies provide further evidence showing reduced tumor cell migration in response to epidermal growth factors (EGF) after depletion of PDK1 despite normal expression of cell surface EGF receptor
Summary
Invasion and metastasis are the major causes of mortality and morbidity in cancer [1]. Recent studies suggest that epidermal growth factors (EGF), secreted by macrophages along blood vessel walls, induces intravasation of primary tumor cells into circulation, whereas chemokines, secreted from bone, lymph nodes, and brain, actively attract extravasation of circulating tumor cells [3, 4]. Both intravasation and extravasation are mediated by chemotaxis, the capacity of a cell to detect an extracellular gradient of chemical stimuli and to migrate to the higher concentration site [3, 5]. Shared chemotactic signaling molecules will provide valuable targets for antimetastasis therapies
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