RT Journal Article
SR Electronic
T1 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
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1062
OP 1070
DO 10.1124/jpet.104.070938
VO 311
IS 3
A1 Jee Hyun Um
A1 Joong Keun Kwon
A1 Chi-Dug Kang
A1 Mi Ju Kim
A1 Dong Sik Ju
A1 Jae Ho Bae
A1 Dong Wan Kim
A1 Byung Seon Chung
A1 Sun Hee Kim
YR 2004
UL http://jpet.aspetjournals.org/content/311/3/1062.abstract
AB 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-κB, 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. The American Society for Pharmacology and Experimental Therapeutics