DJ-1 promotes invasion and metastasis of pancreatic cancer cells by activating SRC/ERK/uPA

Abstract

A major hallmark of pancreatic ductal adenocarcinoma (PDAC) is extensive local tumor invasion and early systemic dissemination. DJ-1 has been shown to prevent cell death via the Akt pathway, thereby playing an important role in cancer progression and Parkinson's disease development. Here, we investigated the role of DJ-1 in tumor invasion and metastasis of pancreatic cancer and showed that DJ-1 is upregulated in 68.5% of pancreatic cancer specimens, correlated with tumor stage and predictive of short overall survival. Knockdown of DJ-1 expression in two PDAC cell lines reduced cell migration and invasion potential in vitro and inhibited metastasis in vivo. Knockdown of DJ-1 led to cytoskeleton disruption and diminished urokinase plasminogen activator (uPA) activity and expression, without affecting plasminogen activator inhibitor-1 and uPA receptor (uPAR) expression. All these effects were reversed by restoration of DJ-1 expression. In determining the pathway through which DJ-1 regulated cell migration and invasion, DJ-1 was found not to regulate Akt phosphorylation. Rather, it promoted extracellular signal-regulated kinase (ERK) and SRC phosphorylation. Inhibition of the ERK pathway in PDAC mimicked the effects of DJ-1 on cell migration, invasion, actin cytoskeleton and uPA/uPAR system and abolished the effects on promoting PDAC cell invasion and migration. These data represent the first identification of an important function of DJ-1, which is to regulate the invasion and metastasis properties of PDAC through the ERK/uPA cascade.

Epidermal Growth Factor-dependent Activation of the Extracellular Signal-regulated Kinase Pathway by DJ-1 Protein through Its Direct Binding to c-Raf Protein

“…Although oxidation of Cys-106 with an SOH form is not ruled out due to specific recognition of Cys-106 with SO 2 H and SO 3 H forms by the antioxidized DJ-1 antibody used in this study, EGF treatment does not induce highly oxidized forms of DJ-1, suggesting that oxidation of Cys-106 with an SO 2 H form is not necessary for DJ-1 to activate c-Raf. DJ-1 enhances the ERK pathway upon various stimuli (11)(12)(13), and DJ-1 is an activated ras-cooperating oncogene (1). This study showed for the first time that DJ-1 activates the ERK pathway through direct activation of c-Raf.…”

“…Statistical analyses were performed using one-way analysis of variance followed by unpaired Student's t test. (1), and DJ-1 activates the ERK pathway (11)(12)(13). We therefore examined the binding activity of DJ-1 to H-Ras and c-Raf.…”

The Oxidation States of DJ-1 Dictate the Cell Fate in Response to Oxidative Stress Triggered by 4-HPR: Autophagy or Apoptosis?

“…It has been reported that DJ-1 is involved in the progression of early onset of familial Parkinson's disease, and recently, increasing reports have demonstrated its connection to cancer (16,29,48). The interaction between ASK1 and DJ-1 has been observed by several groups.…”

“…Although increasing reports have indicated its connection to cancer (16,29,48), DJ-1 has only been proposed as a biomarker for cancer diagnosis, prognosis, metastasis, or the sensitivity of chemotherapy. In the present study, we demonstrate that knocking down the expression of DJ-1 enhances the sensitivity of tumor cells to 4-HPR both in vitro and in vivo (Fig.…”

SG2NA enhances cancer cell survival by stabilizing DJ-1 and thus activating Akt

“…Increased DJ-1 and Akt activities have been associated with cancer development [22]. In view of our recent observation that SG2NA modulates cell cycle progression (unpublished) and it recruits Akt and DJ-1 under oxidative stress [11]; we tested whether association of SG2NA, DJ-1 and Akt is also enhanced in cancer cells.…”