RESUMEN

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.

Asunto(s)

Proteínas Portadoras/metabolismo , Regulación hacia Abajo , Proteínas de la Membrana/metabolismo , Neoplasias Experimentales/patología , Sirtuinas/metabolismo , Succinatos/química , Hormonas Tiroideas/metabolismo , Células A549 , Animales , Proteínas Portadoras/química , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Lisina/metabolismo , Proteínas de la Membrana/química , Ratones , Neoplasias Experimentales/metabolismo , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Hormonas Tiroideas/química , Proteínas de Unión a Hormona Tiroide

RESUMEN

Objective To evaluate the efficacy and safety of DA-EPOCH-R protocol for patients with B-cell non-hodgkin lymphoma (NHL). Methods 43 patients with B-cell NHL received DA-EPOCH-R protocol, and their efficacy and adverse reactions were analyzed. Results 43 patients received a total of 203 cycles of chemotherapy and the median chemotherapy cycle was 6 (2ˉ8 cycles). 32 patients (74.4%) achieved complete remission (CR) after 2ˉ4 cycles of chemotherapy. A further analysis found that age ≤60 years and>60 years, stageⅠ/Ⅱand stageⅢ/Ⅳ, germinal center B-cell (GCB), non-GCB, double expression lymphoma (DEL) and non-DEL patients had no significant differences (P> 0.05). With a median follow-up of 40 months (9ˉ62 mouths), the overall survival (OS) rate of 1-year and 3-year was 97.6 % and 92.8 % respectively. The major toxicity of DA-EPOCH-R protocol was hematologic toxicity. Other toxicities were mild, and no treatment-related deaths occurred. At the end of follow-up, no secondary tumors were found. Conclusions DA-EPOCH-R protocol is an effective and safe protocol for patients with NHL. The result shows that the curative effect of patients in stageⅢandⅣis similar to the patients in stageⅠandⅡ.

RESUMEN

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.