Abstract
Epidermal growth factor (EGF) may increase cell motility, an event implicated in cancer cell invasion and me-tastasis. However, the underlying mechanisms for EGF-induced cell motility remain elusive. In this study, we found that EGF treatment could activate Ras-related C3 botulinum toxin substrate 1 (Rac1), PI3K/Akt and p21-actived kinase (PAK1) along with cell migration. Ectopic expression of PAK1 K299R, a dominant negative PAK1 mutant, could largely abolish EGF-induced cell migration. Blocking PI3K/Akt signalling with LY294002 or Akt siRNA remarkably inhibited both EGF-induced PAK1 activation and cell migration. Furthermore, expression of dominant-negative Rac1 (T17N) could largely block EGF-induced PI3K/Akt-PAK1 activation and cell migration. Interestingly, EGF could induce a significant production of ROS, and N-acetyl-L-cysteine, a scavenger of ROS which abolished the EGF-induced ROS generation, cell migration, as well as activation of PI3K/Akt and PAK, but not Rac1. Our study demonstrated that EGF-induced cell migration involves a cascade of signalling events, including activation of Rac1, generation of ROS and subsequent activation of PI3K/Akt and PAK1.
Highlights
Breast cancer is one of the most common malignancies afflicting women worldwide[1]
Delineating the signaling pathways that regulate cancer cell migration could provide a basis for designing future therapeutic strategies for blocking breast cancer metastasis in patients. p21-activated kinase (PAK1), the best-characterized member of the PAK family, is a serine/threonine protein kinase, which interacts with cell division control protein 42 homolog (Cdc42) and Ras-related C3 botulinum toxin substrate 1 (Rac1)[5]
We investigated whether Rac1/Reactive oxygen species (ROS) regulates phosphatidylinositol 3-kinase (PI3K)/Akt and PAK1 signaling and is critically linked to Epidermal growth factor (EGF)-mediated breast cancer cell migration
Summary
Breast cancer is one of the most common malignancies afflicting women worldwide[1]. Lymph node and hematogenous metastasis occurs at the early stage of breast cancer and is the principal cause of mortality of breast cancer patients[2,3,4]. P21-activated kinase (PAK1), the best-characterized member of the PAK family, is a serine/threonine protein kinase, which interacts with cell division control protein 42 homolog (Cdc42) and Ras-related C3 botulinum toxin substrate 1 (Rac1)[5]. Delineating the signaling pathways that regulate cancer cell migration could provide a basis for designing future therapeutic strategies for blocking breast cancer metastasis in patients. It functions as a downstream node for various oncogenic signaling pathways[6,7]. Increased PAK1 expression and activity in breast tumor is well documented[8], whereas inhibition of PAK1 activity in breast cancer cells leads to
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