Carcinogenicity of carbon nanotubes is a major concern but has not been well addressed due to the lack of experimental models. Here, we show that chronic exposure to single-walled carbon nanotubes causes malignant transformation of human lung epithelial cells. The transformed cells induce tumorigenesis in mice and exhibit an apoptosis resistant phenotype characteristic of cancer cells. This study provides new evidence for carbon nanotube-induced carcinogenesis and indicates the potential role of p53 in the process.

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...

Lung cancer is one of the most common causes of cancer death due to its high metastasis potential. The process of cancer migration is an early step that is required for successful metastasis. The discovery and development of natural compounds for cancer therapy have garnered increasing attention in recent years. Gigantol (1) is a bibenzyl compound derived from the Thai orchid, Dendrobium draconis. It exhibits significant cytotoxic activity against several cancer cell lines; however, until recently, the role of 1 on tumor metastasis has not been characterized. This study demonstrates that 1 suppresses the migratory behavior of non-small cell lung cancer H460 cells. Western blot analysis reveals that 1 down-regulates caveolin-1 (Cav-1), activates ATP-dependent tyrosine kinase (phosphorylated Akt at Ser 473), and cell division cycle 42 (Cdc42), thereby suppressing filopodia formation. The inhibitory effect of 1 on cell movement is also exhibited in another lung cancer cell line, H292, but not in normal human keratinocytes (HaCat). The inhibitory activity of 1 on lung cancer migration suggests that this compound may be suitable for further development for the treatment of cancer metastasis.

SignificanceEach neuron forms a single axon and multiple dendrites, and this configuration is important for wiring the brain. How only a single axon extends from a neuron, however, remains unknown. This study demonstrates that CAMSAP3, a protein that binds the minus-end of microtubules, preferentially localizes along axons in hippocampal neurons. Remarkably, mutations of CAMSAP3 lead to production of multiple axons in these neurons. In attempts to uncover mechanisms underlying this abnormal axon extension, the authors found that CAMSAP3-anchored microtubules escape from acetylation, a process mediated by α-tubulin acetyltransferase-1, and depletion of this enzyme abolishes abnormal axon formation in CAMSAP3 mutants. These findings reveal that CAMSAP3 controls microtubule dynamics, preventing tubulin acetylation; this mechanism is required for single-axon formation.

Anoikis, an apoptosis triggered by loss of cell anchorage, has been shown to be a principal mechanism of inhibition of tumor metastasis. Recently, anti-apoptotic Bcl-2 and Cav-1 proteins have been demonstrated to be highly associated with tumor metastasis and apoptosis resistance. Curcumin, a major active component of turmeric, Curcuma longa, has been shown to inhibit neoplastic evolution and tumor progression; however, the underlying mechanisms are unclear. In this study, we investigated the effect of curcumin on cell anoikis as a possible mechanism of anti-tumorigenic action of curcumin, and evaluated the potential role of Bcl-2 and Cav-1 in this process. Our results showed that ectopic expression of either Bcl-2 or Cav-1 induced anoikis resistance of lung carcinoma H460 cells. Curcumin downregulated Bcl-2 protein during anoikis and sensitized the cells to detachment-induced apoptosis, whereas it had no significant effect on Cav-1 protein expression. Bcl-2 down-regulation as well as anoikis enhancement by curcumin were inhibited by superoxide anion scavenger, Mn(III)tetrakis(4-benzoic acid) porphyrin chloride, but were unaffected by other ROS scavengers including catalase and deferoxamine, suggesting that superoxide anion is a key player in the downregulation of Bcl-2 by curcumin. Furthermore, we provided evidence that curcumin decreased Bcl-2 level through ubiquitin-proteasomal degradation which sensitized cells to detachment-induced apoptosis. These findings indicate a novel pathway for curcumin regulation of Bcl-2 and provide a key mechanism of anoikis regulation that may be exploited for metastatic cancer treatment.