Proteasome inhibitor MG132 enhances the antigrowth and antimetastasis effects of radiation in human nonsmall cell lung cancer cells.
The current treatment for advanced nonsmall cell lung cancer (NSCLC) remains unsatisfactory due to resistance to chemotherapy and ionizing radiation. The ubiquitin-proteasome system (UPS) regulates multiple cellular processes that are crucial for the proliferation and survival of all kinds of cells. Carbobenzoxyl-leucinyl-leucinyl-leucinal-H (MG132), a specific and selective reversible inhibitor of the 26S proteasome, represents a novel approach for cancer therapy. However, whether MG132 can potentiate the effect of radiation against the growth and metastasis of NSCLC is not clear. We found that MG132 inhibited the proliferation of human NSCLC cell lines (A549 and H1299) in a dose- and time-dependent manner by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Then MG132 at a nontoxic dose (100 nM) was selected for following studies. Pretreatment of A549 and H1299 cells with 100 nM MG132 before ionizing radiation (IR) potentiated the anticancer effect of IR. Moreover, pretreatment with 100 nM MG132 before IR-enhanced radiation induced cell cycle arrest by decreased CyclinD1 but increased Wee1 expression in A549 and H1299 cells. In addition, pretreatment of MG132 combined with IR significantly suppressed cell migration and invasion abilities in NSCLC cell lines, which was accompanied by decreased expression of matrix metalloproteinase (MMP)-2 and MMP-9 in NSCLC cell lines. Taken together, our results demonstrate that MG132 enhances the antigrowth and antimetastatic effects of irradiation in NSCLC cells by modulating expression of cell cycle and invasion- related genes.
School of Radiation Medicine and Protection and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, China.
Jing
J
Liu
Wenhao
W
Shen
Yiting
Y
Tang
Jundong
J
Zhou
Ming
M
Li
Wei
W
Zhu
Hongying
H
Yang
Jinchang
J
Wu
Shuyu
S
Zhang
Jianping
J
Cao
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology / Q000532:radiotherapy* / Q000556:secondary; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D019938:Cyclin D1 / Q000235:genetics; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology* / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009687:Nuclear Proteins / Q000235:genetics; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011836:Radiation Tolerance
D000970:Antineoplastic Agents; C530104:CCND1 protein, human; D018797:Cell Cycle Proteins; D007976:Leupeptins; D016328:NF-kappa B; D009687:Nuclear Proteins; D061988:Proteasome Inhibitors; D019938:Cyclin D1; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde