Differential effect of proIGF-II and IGF-II on resveratrol induced cell death by regulating survivin cellular localization and mitochondrial depolarization in breast cancer cells.
Insulin-like growth factor II (IGF-II) plays a pivotal role in fetal and cancer development by signaling through the IGF-I and insulin receptors and activating the estrogen signaling cascade. We previously showed that precursor IGF-II (proIGF-II, the predominant form expressed in cancer) and not mature IGF-II (mIGF-II) blocks resveratrol (RSV) (a phytoalexin/anticancer agent)-induced cell death in MCF-7 cells. We hypothesize that proIGF-II regulates antiapoptotic proteins and/or the mitochondria to inhibit RSV actions and promote cell survival. This study examines the effect of mIGF-II and proIGF-II on survivin expression and mitochondrial polarization in response to RSV. RSV inhibits survivin expression and stimulates mitochondrial depolarization, caspase 7 activation and cell death. These effects were completely blocked by the addition of proIGF-II. RSV treatment had no effect on transfected MCF-7 cells constitutively expressing proIGF-II, while IGF-II siRNA transfection decreased survivin levels. Our results provide new insights for the potential use of proIGF-II as target for new anticancer therapies.
Singh
S Kalla
SK
Center for Health Disparities Research, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
Moretta
D
D
Almaguel
F
F
Wall
N R
NR
De León
M
M
De León
D
D
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007335:Insulin-Like Growth Factor II / Q000502:physiology*; D053078:Membrane Potential, Mitochondrial; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000502:physiology; D009363:Neoplasm Proteins / Q000378:metabolism*; D011498:Protein Precursors / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D000077022:Survivin
D000972:Antineoplastic Agents, Phytogenic; C107489:BIRC5 protein, human; C035170:IGF2 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011498:Protein Precursors; D013267:Stilbenes; D000077022:Survivin; D007335:Insulin-Like Growth Factor II; D053179:Caspase 7; D000077185:Resveratrol