TRF2 promotes multidrug resistance in gastric cancer cells.
The role of telomere in drug resistance has not been clearly understood. Recent studies have been focused on telomerase activity and telomere length, but the findings are still controversial. It's been found that DNA double-strand breaks induced by anticancer drugs or irradiation increase TRF2 expression as an early response to DNA damage, which inhibits activation of ATM-dependent DNA damage response network, indicating TRF2 might probably be a general DNA-repair factor rather than merely a telomere-binding factor. In this study, the possible involvement of telomerase, telomere and TRF2 in DNA damage response and drug resistance was investigated. Telomere length was found elongated in multidrug-resistant variants of gastric cancer cell line SGC7901 treated with adriamycin or etoposide, however, drug-treatment per se had no effect on telomere length. Telomerase activity and TRF2 expression were upregulated after treatment, but not TRF1. TRF2 upregulation was more dramatic in drug-resistant cells and occurred before the expression of ATM, gammaH2AX and p53. Moreover, TRF2 inhibited the expression of ATM-dependent DSB responsive genes. Inhibition of TRF2 expression by RNA interference in drug-resistant cells partially reversed its resistance phenotype and overexpression of TRF2 in SGC7901 promoted its resistance phenotype. Taken together, current results indicate that TRF2 plays an important role in DNA damage response, and is involved in drug resistance of gastric cancer. Further study of the biological functions of TRF2 might be helpful to dissect the molecular mechanism of multiple drug-resistance and generate novel target to overcome it.
Ning
Hanbing
H
State Key Laboratory of Cancer Biology, Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China.
Li
Tingting
T
Zhao
Lina
L
Li
Ting
T
Li
Jichang
J
Liu
Jie
J
Liu
Zhiguo
Z
Fan
Daiming
D
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D010957:Plasmids / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D016615:Telomere / Q000502:physiology*; D035341:Telomeric Repeat Binding Protein 2 / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D034741:RNA, Small Interfering; D035341:Telomeric Repeat Binding Protein 2; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases