ABSTRACT
Tumor cells trends to express high level of pyruvate kinase M2 (PKM2). The inhibition of PKM2 activity is needed for antioxidant response by diverting glucose flux into the pentose phosphate pathway and thus generating sufficient reducing potential. Here we report that PKM2 is succinylated at lysine 498 (K498) and succinylation increases its activity. SIRT5 binds to, desuccinylates and inhibits PKM2 activity. Increased level of reactive oxygen species (ROS) decreases both the succinylation and activity of PKM2 by increasing its binding to SIRT5. Substitution of endogenous PKM2 with a succinylation mimetic mutant K498E decreases cellular NADPH production and inhibits cell proliferation and tumor growth. Moreover, inhibition of SIRT5 suppresses tumor cell proliferation through desuccinylation of PKM2 K498. These results reveal a new mechanism of PKM2 modification, a new function of SIRT5 in response to oxidative stress which stimulates cell proliferation and tumor growth, and also a potential target for clinical cancer research.
Subject(s)
Carrier Proteins/metabolism , Down-Regulation , Membrane Proteins/metabolism , Neoplasms, Experimental/pathology , Sirtuins/metabolism , Succinates/chemistry , Thyroid Hormones/metabolism , A549 Cells , Animals , Carrier Proteins/chemistry , Cell Proliferation , Gene Expression Regulation, Neoplastic , HEK293 Cells , Humans , Lysine/metabolism , Membrane Proteins/chemistry , Mice , Neoplasms, Experimental/metabolism , Oxidative Stress , Reactive Oxygen Species/metabolism , Thyroid Hormones/chemistry , Thyroid Hormone-Binding ProteinsABSTRACT
Objective To determine the efficacy and toxicity of docetaxel in patients with paclitaxel-resistant advanced non-small cell lung cancer (NSCLC). Methods The clinical data from 15 patients with NSCLC who were admitted in the Shanghai Chest Hospital from January 2005 to May 2008 were retrospectively analyzed. The effects and toxicities of the second-line treatment were assessed. The progression-free survival time(PFS) and overall survival time(OS) were analyzed. Results The disease control rate was 66.7 %, with a progression-free survival time of 6 months, and a overall survival time of 17.3 months. The 1-year survival rate was 63.3 %. The toxic effects were as expected. Conclusion The doeetaxel-based agent is active in patients with paelitaxel-resistant advanced NSCLC.
ABSTRACT
The performance status(PS)≥2 patients with non-small cell lung cancer(NSCLC) are short of effective management.The phase Ⅱ/Ⅲ clinical trails of target therapy of anti EFGR of VEGFR have already got promise results.This article expatiates the actuality and development of the chemotherapy and novel target therapy for the PS≥2 patients with NSCLC.
