Down-regulation of inhibitor of apoptosis proteins by deguelin selectively induces apoptosis in breast cancer cells.
The identification of differentially regulated apoptotic signals in normal and tumor cells allows the development of cancer cell-selective therapies. Increasing evidence shows that the inhibitor of apoptosis (IAP) proteins survivin and XIAP are highly expressed in tumor cells but are absent or have very low levels of expression in normal adult tissues. We found that inhibiting AKT activity with 10 to 100 nM deguelin, a small molecule derived from natural products, markedly reduced the levels of both survivin and XIAP, inducing apoptosis in human breast cancer cells but not in normal cells. It is noteworthy that we detected an elevated level of cleaved poly(ADP-ribose) polymerase, a signature of caspase activation, without a significant increase in caspase activity in deguelin-treated cancer cells. Our results suggest that severe down-regulation of the IAPs by deguelin releases their inhibitory activity over pre-existing active caspases present in cancer cells, inducing apoptosis without the need for further caspase activation. Because normal cells have very low levels of p-AKT, XIAP, survivin, and pre-existing caspase activity, deguelin had little effect on those cells. In addition, we found that combining deguelin with chemotherapy drugs enhanced drug-induced apoptosis selectively in human tumor cells, which suggests that deguelin has great potential for chemosensitization and could represent a new therapeutic agent for treatment of breast cancer.
Peng
Xiang-Hong
XH
Department of Surgery, Winship Cancer Institute, Emory University School of Medicine, Clinic C, Room C-4088, 1365 C Clifton Road, NE Atlanta, GA 30322, USA.
Karna
Prasanthi
P
O'Regan
Ruth M
RM
Liu
Xiuju
X
Naithani
Rajesh
R
Moriarty
Robert M
RM
Wood
William C
WC
Lee
Ho-Young
HY
Yang
Lily
L
D017209:Apoptosis; D001943:Breast Neoplasms / Q000473:pathology; D002455:Cell Division; D045744:Cell Line, Tumor; D003114:Colony-Forming Units Assay; D017931:DNA Primers; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000235:genetics; D009363:Neoplasm Proteins / Q000187:drug effects / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012402:Rotenone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism
C107489:BIRC5 protein, human; D017931:DNA Primers; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D012402:Rotenone; C107676:deguelin