Regulation of Lung Cancer Cell Migration and Invasion by Reactive Oxygen Species and Caveolin-1

Abstract

The acquired capability of tumor cells to migrate and invade neighboring tissues is associated with high metastatic potential and advanced stage of cancers. Recently, signaling molecules such as reactive oxygen species (ROS) and caveolin-1 (Cav-1) have been implicated in the aggressive behavior of cancer cells. However, the roles of specific ROS in cancer cell migration and Cav-1 regulation are unclear. We demonstrate here that Cav-1 plays an important role in the migration and invasion of human lung carcinoma H460 cells and that these effects are differentially regulated by cellular ROS. Using various known inhibitors and donors of ROS, we found that different ROS have different effects on Cav-1 expression and cell migration and invasion. Superoxide anion and hydrogen peroxide down-regulated Cav-1 expression and inhibited cell migration and invasion, whereas hydroxyl radical up-regulated the Cav-1 expression and promoted cell migration and invasion. The down-regulating effect of superoxide anion and hydrogen peroxide on Cav-1 is mediated through a transcriptionindependent mechanism that involves protein degradation via the ubiquitin-proteasome pathway. These results indicate the essential role of different ROS in cancer cell motility and through Cav-1 expression, which may provide a key mechanism controlling tumor progression and metastasis. The upregulation of Cav-1 and cell motility by hydroxyl free radical suggests an important role of this ROS as a positive regulator of tumor progression.Cancer cell migration and invasion are initial steps in metastasis that is a primary cause of cancer-related death. During metastasis, primary tumor cells migrate and invade neighboring tissues and enter the circulation to establish new or secondary tumor sites (1-3). Increasing evidence suggests that signaling molecules presenting in the tumor microenvironment have a significant impact on the migratory properties of cancer cells (4,5 Caveolin-1 (Cav-1) is an essential structural protein component of the plasma membrane microdomains called caveolae. It has been shown to function in vesicular trafficking, signal transduction, and tumor progression. Cav-1 interacts with several signaling molecules, including Ha-Ras, Src family tyrosine kinases, G protein ␣ subunits, and protein kinase C (20 -23). Increased expression of Cav-1 has been observed in lung adenocarcinoma and prostate cancer, which are associated with their invasiveness (24 -26). In lung carcinoma, the elevated Cav-1 expression is also associated with an increase in metastatic capacity and poor survival of patients (26 -28). On the other hand, Cav-1 has been shown to have a suppressive effect on pancreatic and breast cancer cell motility (29 -31). Thus, the role of Cav-1 in cancer cell migration and metastasis remains unclear and appears to be cell type-dependent.Increased oxidative stress and ROS production have also been associated with many human metastatic tumors, including the lung (32, 33), breast (34), prostate (35), colon (36), and ovary (37). ROS such as s...

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“…Additional mutations have been described in breast cancer since then [39]. Also, Caveolin-1 expression is regulated at the posttranscriptional level in a differential manner by ROS species and subsequent proteasome-mediated degradation [40]. To what extent this might be a relevant mechanism in the tumor environment remains to be established.…”

Tumor metabolism, cancer cell transporters, and microenvironmental resistance

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