No abstract

Inactivation of tumor suppressors is among the rate-limiting steps in carcinogenesis that occur during the tumor promotion stage. The translation inhibitor programmed cell death 4 (Pdcd4) suppresses tumorigenesis and invasion. Although Pdcd4 is not mutationally inactivated in human cancer, the mechanisms controlling Pdcd4 inactivation during tumorigenesis remain elusive. We report that tumor promoter 12-Otetradecanoylphorbol-13-acetate exposure decreases protein levels of Pdcd4 in mouse skin papillomas and keratinocytes as well as in human HEK293 cells. This decrease is attributable to increased proteasomal degradation of Pdcd4 and is mediated by protein kinase C-dependent activation of phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin-p70 S6K

Oxidative stress is known to cause tumorigenesis through induction of DNA and lipid damage. It also promotes cancer progression through a largely unknown mechanism. Sulfiredoxin (Srx) is a novel oxidative stress-induced antioxidant protein whose function in tumorigenesis and cancer progression has not been well studied. We report that Srx is highly expressed in human lung cancer. Knockdown of Srx reduces anchorage-independent colony formation, cell migration, and invasion of human lung cancer cells. Srx preferentially interacts with Peroxiredoxin (Prx) IV relative to other Prxs due to its intrinsic higher binding affinity. Knockdown of Prx IV recapitulates the phenotypic changes of depleting Srx. Disruption or enhancement of the Srx-Prx IV axis leads respectively to reduction or acceleration of tumor growth and metastasis formation in vivo. Through identification and validation of the downstream mediators we unraveled the Srx-mediated signaling network that traverses AP-1-activating and other phosphokinase signaling cascades. Our work reveals that the Srx-Prx IV axis is critical for lung cancer maintenance and metastasis, suggesting that targeting the Srx-Prx IV axis may provide unique effective strategies for cancer prevention and treatment.oncogene | signal transduction L ung cancer is the most common form of human cancer and is the leading cause of cancer mortality worldwide. Despite recent progress in early detection and combined therapeutic strategies, the overall survival rate of patients has not been significantly improved (1). Many risk factors, including the exposure to tobacco smoke, have been identified as causally related to lung carcinogenesis in patients. Tobacco smoke contains a number of carcinogens, and metabolism of these carcinogens generates active metabolites directly leading to formation of DNA adducts and the accumulation of oxygen-free radicals that induce oxidative stress that contributes significantly to tumorigenesis and cancer progression (2).Oxygen-free radicals, including reactive oxygen species (ROS) and reactive nitrogen species, have been shown to be causally related to cancer progression and metastasis. However, the molecular mechanisms of oxidative stress in cancer maintenance and metastases formation are still not well understood, due in part to the dual roles of ROS as both deleterious and beneficial species in cancer cells. Under physiological conditions ROSinduced oxidative stress response causes cellular senescence and apoptosis. Cancer cells have an enhanced defense system characterized by intrinsically higher expression of antioxidant proteins, and ROS are more likely to function as mediators of intracellular signaling cascades that are critical for maintenance of tumor phenotypes (3). Sulfiredoxin (Srx), or neoplastic progression 3, was previously identified as a differentially expressed gene with unknown function that distinguished transformed and transformation-sensitive from transformation-resistant mouse epidermal cells (4). More recent studies substantiate that Srx...