论文部分内容阅读
Cadmium (Cd), which presents in cigarette smoke and widely-distributed in the environment, is one of the highly toxic metals and causative factor for lung cancer development.However, a more unified molecular mechanism of action associated with its carcinogenic properties is still lacking.Protein kinases are critical modulators required for controlling cellular metabolism, proliferation and differentiation;and dysregulation or hyperactivation of protein kinase has been shown to occur in various types of human cancers.Using rat lung epithelial cells (LECs) as a model, our results showed that LECs developed resistance to apoptosis during cadmium adaptation possibly due to desensitization of the c-Jun NH2-terminal kinase (JNK) pathway.JNK pathway desensitization in Cd-adapted LECs was not due to the up-regulation of MAPK phosphatase-1 (MKP-1) expression, indicating the nonessential role of MKP-1 in cadmium adaptation in LECs.Therefore, we further study the resistant factors by comparative proteomics.Interestingly, we showed that two intermediate filament proteins, cytokeratin 8 (CK8) and cytokeratin 14 (CK14), were increased significantly and stably maintained only in the adapted cells but not in cadmium-treated parental cells.It has been documented that CK8/cytokeratin 18 provided resistance to tumor necrosis factor (TNF)-induced apoptosis and CK14 may function as an inhibitor of TNF-TNF receptor 1 (TNFR1) signaling through an association with TNFR1-associated death domain protein, suggesting that up-regulation of CK8 and CK14 may be responsible for apoptotic resistance.Finally, we showed that small interfering RNA-specific knockdown of CK8 in cadmium-adapted cells attenuated the cadmium resistance, indicating the potential role of CK8 in cadmium resistance.This acquired self-resistance to apoptosis could account for cadmium-induced carcinogenesis, as this promotes neoplastic cell survival as well as subsequent clonal expansion and then progression of tumor development.Thus, increased expression of these cytokeratins represents an adaptive survival mechanism that resists cadmium-induced apoptosis and it is unprecedented that cells respond to long-term cadmium exposure by modulating keratin dynamics.