Reversal of drug resistance in breast cancer cells by transglutaminase 2 inhibition and nuclear factor-kappaB inactivation.
Induction of transglutaminase 2 (TGase 2) by epidermal growth factor (EGF) in human breast cancer cells increases their oncogenic potential and chemoresistance. The role of TGase 2 in the development of these tumor-related phenotypes remains to be elucidated, but it has been shown that expression of a dominant-negative form of TGase 2 reverses EGF-mediated chemoresistance in breast cancer cells. We examined several different breast cancer cell lines, representing both EGF receptor (EGFR)-positive and EGFR-negative breast cancers, and found that doxorubicin-resistant cells had a higher level of TGase 2 compared with doxorubicin-sensitive cells independent of the EGFR expression level. TGase 2 inhibition increased the chemosensitivity of drug-resistant cells, concomitant with a decrease in nuclear factor-kappaB (NF-kappaB) activity. Increasing the level of TGase 2 in drug-sensitive cells by transient transfection reduced the level of inhibitory subunit alpha of NF-kappaB (IkappaBalpha) and increased NF-kappaB activity in these cells. Inhibition of TGase 2 in drug-resistant cells by RNA interference increased the levels of IkappaBalpha, and this correlated with a shift in the accumulation of NF-kappaB from the nucleus to the cytosol. We recently showed that TGase 2 activated NF-kappaB through polymerization and depletion of free IkappaBalpha during inflammation. Therefore, increased expression of TGase 2 and subsequent activation of NF-kappaB may contribute to drug resistance in breast cancer cells independently of EGF signaling.
Kim
Dae-Seok
DS
Molecular Oncology Branch, Division of Basic Sciences, Research Institute and Cancer Biostatistics Branch, Center for Clinical Trials, National Cancer Center, Goyang, Kyonggi-do, Republic of Korea.
Park
Sung-Soo
SS
Nam
Byung-Ho
BH
Kim
In-Hoo
IH
Kim
Soo-Youl
SY
D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D004317:Doxorubicin; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D066246:ErbB Receptors; D019204:GTP-Binding Proteins