2018-04-06
Sisi He was selected for an oral presentation at ENDO 2018. She was awarded Endocrine Society Outstanding Abstract Award & EndoCareers Early Career Forum Travel Award.
Abstract:
The poor prognosis of ovarian cancer patients (5-year survival is less than 50%) is due, in part, to progressive development of resistance to chemotherapy. Overexpression of the difficult to target protein, multidrug resistance protein 1 (MDR1)/P-glycoprotein, is a common resistance mechanism. We describe BHPI, a novel estrogen receptor α (ERα) biomodulator that inactivates MDR1 and restores sensitivity of highly resistant ovarian cancer cells to therapeutically relevant concentrations of taxanes. 30-70% of ovarian tumors are ERα+, but antiestrogens are usually ineffective. BHPI is a first-in-class non-competitive ERα biomodulator that strongly inhibits proliferation of anchorage-dependent and anchorage-independent, antiestrogen-resistant, ERα positive ovarian cancer cells (CaOV-3 and PEO4). BHPI works by distorting a recently unveiled signaling pathway, in which estrogen-ERα elicits a rapid, moderate, and transient “anticipatory” activation of the endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR). BHPI, acting via ERα, elicits sustained hyperactivation of the UPR, converting it from cytoprotective to cytotoxic. BHPI-ERα strongly activates plasma membrane phospholipase C γ (PLCγ). The activated PLCγ produces inositol triphosphate (IP3), which bind to and open EnR IP3 receptors (IP3R) resulting in rapid efflux of Ca2+ stored in EnR lumen into the cytosol. This strongly activates the UPR. To restore normal calcium homeostasis, powerful ATP-dependent EnR SERCA Ca2+ pumps, which pump Ca2+ from cytosol into the EnR, are activated. Because the EnR Ca2+ IP3R channels are open, the Ca2+pumped into the EnR leaks back out, leading to an ATP-depleting futile cycle. Reducing intracellular ATP with BHPI nearly abolishes MDR1-mediated efflux in multidrug resistant OVCAR-3 ovarian cancer cells. BHPI increased sensitivity of the highly multidrug resistant OVCAR-3 cells to killing by paclitaxel by more than a thousand fold. BHPI was also effective in other multidrug resistance models. Studies evaluating the ability of BHPI to restore sensitivity to taxanes in physiologically relevant models are underway. Because the UPR is nearly inactive in most normal cells and is overexpressed in ERα+ breast and ovarian tumors, this represents an innovative strategy for selectively targeting multidrug resistance in ovarian cancer and breast cancer.