Relationship between antiapoptotic molecules and metastatic potency and the involvement of DNA-dependent protein kinase in the chemosensitization of metastatic human cancer cells by epidermal growth factor receptor blockade.
The failure to treat metastatic cancer with multidrug resistance is a major problem for successful cancer therapy, and the molecular basis for the association of metastatic phenotype with resistance to therapy is still unclear. In this study, we revealed that various metastatic cancer cells showed consistently higher levels of antiapoptotic proteins, including Bcl-2, nuclear factor-kappaB, MDM2, DNA-dependent protein kinase (DNA-PK), and epidermal growth factor receptor (EGFR), and lower levels of proapoptotic proteins, including Bax and p53 than low metastatic parental cells. This was followed by chemo- and radioresistance in metastatic cancer cells compared with their parental cells. EGFR and DNA-PK activity, which are known to be associated with chemo- and radioresistance, were demonstrated to be mutually regulated by each other. Treatment with PKI166, an EGFR inhibitor, suppressed etoposide-induced activation of DNA-PK in A375SM metastatic melanoma cells. In addition, PKI166 enhanced markedly the chemosensitivities of metastatic cancer cell sublines to various anticancer drugs in comparison with those of low metastatic cancer cells. These results suggest that the activities of DNA-PK and EGFR, which is positively correlated with each other, may contribute to metastatic phenotype as well as therapy resistance, and the EGFR inhibitor enhances the effect of anticancer drugs against therapy-resistant metastatic cancer cells via suppression of stress responses, including activation of DNA-PK.
Department of Biochemistry, College of Medicine, Pusan National University, Pusan 602-739, South Korea.
Jee Hyun
JH
Um
Joong Keun
JK
Kwon
Chi-Dug
CD
Kang
Mi Ju
MJ
Kim
Dong Sik
DS
Ju
Jae Ho
JH
Bae
Dong Wan
DW
Kim
Byung Seon
BS
Chung
Sun Hee
SH
Kim
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004357:Drug Synergism; D024202:Electrophoretic Mobility Shift Assay; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005047:Etoposide / Q000494:pharmacology; D019450:Genes, MDR / Q000235:genetics; D006801:Humans; D007202:Indicators and Reagents; D008545:Melanoma / Q000473:pathology; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000503:physiopathology* / Q000532:radiotherapy; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D051381:Rats
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; D007202:Indicators and Reagents; D009687:Nuclear Proteins; D011743:Pyrimidines; D011758:Pyrroles; D011838:Radiation-Sensitizing Agents; D005047:Etoposide; C410026:PKI 166; D066246:ErbB Receptors; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases