Abstract A58: Transcription factor SREBP2 mediates ovarian cancer drug resistance and recurrence
Authors: Galina Karashchuk, Alexander S. Brodsky
Journal: Clinical Cancer Research (2018)

Abstract Ovarian cancer, the most lethal gynecologic malignancy, has a poor prognosis. Existing chemotherapies are challenged by the emergence of drug resistance and metastasis of tumor cells, which obstruct sustained, relapse-free patient cures. Resistance can emerge from pre-existing mutations, secondary mutations, or other nongenetic mechanisms or metabolic adaptations. SREBPs are necessary for cell survival in low-nutrient conditions. SREBP1 predominantly regulates fatty acid and glycolysis while SREBP2 regulates cholesterol metabolism. SREBP2 is a sterol sensitive transcription factor regulating cholesterol homeostasis including the expression of LDLR and HMGCR. Recent reports suggest that SREBP2 may promote mesenchymal and stem-cell states. These observations support our working hypothesis that the regulation of cholesterol and fatty acids through SREBP2 is critical for drug tolerance, resistance, and viability of a cancer stem cell population. We further hypothesize that drug-tolerant ovarian cancer cells depend on SREBP2 to re-enter the cell cycle and proliferate. To test this hypothesis, we assessed the importance of SREBP2 in an in vitro drug tolerant model. Ovarian cancer cells were treated with high concentrations of paclitaxel for 1 week and the surviving cells were examined. SREBP2, HMGCR, and related factors were significantly upregulated in these surviving drug-tolerant cells. To evaluate the function of SREBP2 in drug-tolerant cells, stable cell lines targeting the SREBF2 gene using CRISPR technology were created in OVCAR8. Using this SREBF2-KD line, we assessed the response of ovarian cancer cells to drug treatment under different environments. SREBF2-KD cells were more sensitive to statin and paclitaxel in low-sterol environments compared to control cells. These observations highlight the need for SREBP2 in stressed conditions for cancer cells to survive drug treatment. Moreover, after treatment with high concentrations of paclitaxel, SREBF2-KD cells grew back significantly slower compared to control cells. To characterize the mechanisms controlled by SREBP2, we examined the effects on the cell cycle. We have observed a significant change in the distribution of the cell cycle phases between SREBF2-KD and control cells treated with paclitaxel, which suggests an important role for SREBP2 in ovarian cancer cells’ exit from cell cycle arrest after chemotherapy. To further examine the role of SREBP2 in drug resistance and tumor relapse, we are currently extending these in vitro observations to in vivo models. In summary, our study illustrates the crucial role of cholesterol pathway for ovarian cancer not only under stress conditions such as chemotherapy, but also in return to a high proliferative state upon recurrence. These data suggest that targeting SREBP2 may represent a new approach for sequential therapy to eliminate cancer cells that survive initial treatment. Citation Format: Galina Karashchuk, Alexander S. Brodsky. Transcription factor SREBP2 mediates ovarian cancer drug resistance and recurrence. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A58.