TY - JOUR
T1 - Evidence of securin-mediated resistance to gefitinib-induced apoptosis in human cancer cells
AU - Yu, Sheng Yi
AU - Liu, Huei Fang
AU - Wang, Su Pei
AU - Chang, Chia-Ching
AU - Tsai, Chuan Mei
AU - Chao, Jui-I
PY - 2013/4/25
Y1 - 2013/4/25
N2 - Gefitinib, a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), has been used to treat numerous cancers; however, evidence has shown that cancer cells can become resistant to gefitinib during therapy. Here, we report a human proto-oncogene, securin, which displays resistance to death in cancer cells. Gefitinib treatment decreases securin levels at the protein level by inducing protein instability but did not affect on the securin gene expression. Treatment with gefitinib induced cytotoxicity in various human cancer cell types, including RKO (colon cancer), A549 (lung cancer), BFTC905 (bladder cancer), MCF7 (breast cancer) and A375 (skin cancer). BFTC905 and A549 cells expressed relatively high levels of the phosphorylated and total EGFR proteins; however, A375, MCF7 and RKO cells did not markedly express these proteins. Moreover, following treatment with gefitinib, the securin-wild type cancer cells were more resistant to apoptotic induction than the securin-null cancer cells. Surprisingly, both the securin-wild type and securin-null cancer cells expressed the EGFR protein at similar levels. Treatment with gefitinib induced mitochondrial dysfunction, cytochrome c release, caspase-3 activation and poly (ADP-ribose) polymerase protein cleavage, indicating that apoptosis occurred in these cancer cells. The transfection of a GPF-securin expression vector increased both the proliferation rates and resistance to gefitinib-induced death in these cancer cells. Taken together, these findings demonstrate that the presence of securin promotes resistance to gefitinib-induced apoptosis via an EGFR-independent pathway in human cancer cells.
AB - Gefitinib, a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), has been used to treat numerous cancers; however, evidence has shown that cancer cells can become resistant to gefitinib during therapy. Here, we report a human proto-oncogene, securin, which displays resistance to death in cancer cells. Gefitinib treatment decreases securin levels at the protein level by inducing protein instability but did not affect on the securin gene expression. Treatment with gefitinib induced cytotoxicity in various human cancer cell types, including RKO (colon cancer), A549 (lung cancer), BFTC905 (bladder cancer), MCF7 (breast cancer) and A375 (skin cancer). BFTC905 and A549 cells expressed relatively high levels of the phosphorylated and total EGFR proteins; however, A375, MCF7 and RKO cells did not markedly express these proteins. Moreover, following treatment with gefitinib, the securin-wild type cancer cells were more resistant to apoptotic induction than the securin-null cancer cells. Surprisingly, both the securin-wild type and securin-null cancer cells expressed the EGFR protein at similar levels. Treatment with gefitinib induced mitochondrial dysfunction, cytochrome c release, caspase-3 activation and poly (ADP-ribose) polymerase protein cleavage, indicating that apoptosis occurred in these cancer cells. The transfection of a GPF-securin expression vector increased both the proliferation rates and resistance to gefitinib-induced death in these cancer cells. Taken together, these findings demonstrate that the presence of securin promotes resistance to gefitinib-induced apoptosis via an EGFR-independent pathway in human cancer cells.
KW - Apoptosis
KW - Cancer cells
KW - EGFR
KW - Gefitinib
KW - Securin
UR - http://www.scopus.com/inward/record.url?scp=84876004459&partnerID=8YFLogxK
U2 - 10.1016/j.cbi.2013.03.011
DO - 10.1016/j.cbi.2013.03.011
M3 - Article
C2 - 23523951
AN - SCOPUS:84876004459
SN - 0009-2797
VL - 203
SP - 412
EP - 422
JO - Chemico-Biological Interactions
JF - Chemico-Biological Interactions
IS - 2
ER -