TY - JOUR
T1 - NCTD promotes Birinapant-mediated anticancer activity in breast cancer cells by downregulation of c-FLIP
AU - Zhao, Li
AU - Yang, Guoshan
AU - Bai, Hao
AU - Zhang, Minghui
AU - Mou, Dongcheng
PY - 2017
Y1 - 2017
N2 - Second mitochondria-derived activator of caspases (SMAC) mimetics is a class of new anticancer agents. However, most cancers exhibit de novo or acquired resistance to SMAC mimetics, posting a problem for broad applications in clinic, and highlighting the necessity of exploring combinational strategies to circumvent SMAC mimeticresistance. We here showed that Norcantharidin, a drug that is currently being used in cancer treatment, significantly enhanced SMAC mimetic Birinapant-mediated cell viability inhibition and robustly promoted apoptosis in established breast carcinoma cell lines, as well as in primary breast carcinoma cells. Mechanistically, we revealed that Norcantharidin effectively reduced the levels of two major protein isoforms of cellular FLICE-like inhibitor protein(c-FLIP), namely c-FLIP long (c-FLIPL) and c-FLIP short (c-FLIPS). Moreover, Norcantharidin markedly enhanced Birinapanttriggered caspase-8/caspase-3 cascade. Inhibition of caspase-8 activity by a synthetic peptide Z-IETD-FMK significantly attenuated cell death induction by the combination, suggesting that caspase-8 plays a critical role in the anticancer action. In conclusion, our study suggests that the combination of SMAC mimetics with Norcantharidin represents a novel strategy in breast cancer therapy and warrants further studies.
AB - Second mitochondria-derived activator of caspases (SMAC) mimetics is a class of new anticancer agents. However, most cancers exhibit de novo or acquired resistance to SMAC mimetics, posting a problem for broad applications in clinic, and highlighting the necessity of exploring combinational strategies to circumvent SMAC mimeticresistance. We here showed that Norcantharidin, a drug that is currently being used in cancer treatment, significantly enhanced SMAC mimetic Birinapant-mediated cell viability inhibition and robustly promoted apoptosis in established breast carcinoma cell lines, as well as in primary breast carcinoma cells. Mechanistically, we revealed that Norcantharidin effectively reduced the levels of two major protein isoforms of cellular FLICE-like inhibitor protein(c-FLIP), namely c-FLIP long (c-FLIPL) and c-FLIP short (c-FLIPS). Moreover, Norcantharidin markedly enhanced Birinapanttriggered caspase-8/caspase-3 cascade. Inhibition of caspase-8 activity by a synthetic peptide Z-IETD-FMK significantly attenuated cell death induction by the combination, suggesting that caspase-8 plays a critical role in the anticancer action. In conclusion, our study suggests that the combination of SMAC mimetics with Norcantharidin represents a novel strategy in breast cancer therapy and warrants further studies.
KW - Breast cancer
KW - C-FLIP
KW - Norcantharidin
KW - SMAC mimetic
UR - http://www.scopus.com/inward/record.url?scp=85017515235&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85017515235&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.15848
DO - 10.18632/oncotarget.15848
M3 - Article
C2 - 28460471
AN - SCOPUS:85017515235
SN - 1949-2553
VL - 8
SP - 26886
EP - 26895
JO - Oncotarget
JF - Oncotarget
IS - 16
ER -