Abstract
The migration and invasion inhibitory protein (MIIP) has been discovered recently to have inhibitory functions in cell proliferation and migration. Overexpression of MIIP reduced the intracellular steady-state level of epidermal growth factor receptor (EGFR) protein in lung cancer cells with no effect on EGFR mRNA expression compared to that in the control cells. This MIIP-promoted EGFR protein degradation was reversed by proteasome and lysosome inhibitors, suggesting the involvement of both proteasomal and lysosomal pathways in this degradation. This finding was further validated by pulse-chase experiments using 35S-methionine metabolic labeling. We found that MIIP accelerates EGFR protein turnover via proteasomal degradation in the endoplasmic reticulum and then via the lysosomal pathway after its entry into endocytic trafficking. MIIP-stimulated downregulation of EGFR inhibits downstream activation of Ras and blocks the MEK signal transduction pathway, resulting in inhibition of cell proliferation. The negative correlation between MIIP and EGFR protein expression was validated in lung adenocarcinoma samples. Furthermore, the higher MIIP protein expression predicts a better overall survival of Stage IA-IIIA lung adenocarcinoma patients who underwent radical surgery. These findings reveal a new mechanism by which MIIP inhibits cell proliferation.
Highlights
Lung cancer is the leading cause of cancer death in both men and women worldwide, accounting for over a million deaths annually [1, 2]
epidermal growth factor receptor (EGFR) protein is widely expressed in lung cancer tissues and most lung cancer cell lines, including H1299, A549, and H322, which were used in our experiments
We found that migration and invasion inhibitory protein (MIIP) accelerates EGFR degradation via both proteasomal and lysosomal pathways
Summary
Lung cancer is the leading cause of cancer death in both men and women worldwide, accounting for over a million deaths annually [1, 2]. Epidermal growth factor receptor (EGFR), a member of the c-erbB family, is highly expressed in a variety of human tumors, including nonsmall cell lung cancer (NSCLC), and is implicated in tumor development [3, 4]. A number of abundant ER residents have been identified as chaperones, such as members of the heat shock protein family, including BIP and its co-chaperone partners. They facilitate protein folding, oligomerization, maturation, and posttranslational modifications. After proper folding in the ER, EGFR protein was transported from the ER to the Golgi apparatus. The mature EGFR is transported to the cell membrane
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