Targeting SREBP-driven Transcriptional Programs in Metastatic Prostate Cancer
Faculty Mentor
Avinash Kumar
Major/Area of Research
Pharmacology and Toxicology (Pharmaceutical Sciences)
Description
INTRODUCTION: Metastasis is the major cause of mortality associated with prostate cancer (PCa), and despite the availability of targeted therapeutic agents, metastatic prostate cancer remains a lethal disease. Sterol regulatory element binding proteins (SREBPs) are transcription factors involved in fatty acid and cholesterol synthesis, and when overexpressed, they have been associated with the progression of PCa. Therefore, we hypothesized that the pharmacological inhibition of SREBPs could be an effective therapeutic strategy against metastatic prostate cancer. BF175 is a new stilbene-derivative, boron-containing small molecule inhibitor known to inhibit SREBP activity. The exact mechanism of action of BF-175 in PCa and its efficacy in PCa remains fully elucidated.
METHOD: Prostate Oncomine and cBioportal databases contain prostate cancer patient datasets, which were queried for SREBP mRNA overexpression and copy number alterations. We used 4 PCa cell lines, namely PC3, PC3M, LNCaP, and C4-2B, to conduct our cell viability and proliferation assays, clonogenic survival assay, wound healing assay, trans-well migration, and invasion assays. RESULTS: SREBP inhibition by BF175 significantly reduced cell viability, proliferation, and clonogenic survival in all prostate cancer cell lines tested. Analysis of wound healing, trans-well migration, and invasion assay revealed that BF175 significantly reduced migration and invasion in all PCa cells tested. We also confirmed that BF175 inhibited the expression of SREBPs in the tested prostate cancer cell lines. Of note, BF175 exhibited significantly higher potency as an anticancer agent in more invasive prostate cancer cell lines than their less invasive counterparts.
CONCLUSION: Our results demonstrate that BF175 shows promise as a novel anticancer agent that may improve outcomes in lethal metastatic PCa.
Targeting SREBP-driven Transcriptional Programs in Metastatic Prostate Cancer
INTRODUCTION: Metastasis is the major cause of mortality associated with prostate cancer (PCa), and despite the availability of targeted therapeutic agents, metastatic prostate cancer remains a lethal disease. Sterol regulatory element binding proteins (SREBPs) are transcription factors involved in fatty acid and cholesterol synthesis, and when overexpressed, they have been associated with the progression of PCa. Therefore, we hypothesized that the pharmacological inhibition of SREBPs could be an effective therapeutic strategy against metastatic prostate cancer. BF175 is a new stilbene-derivative, boron-containing small molecule inhibitor known to inhibit SREBP activity. The exact mechanism of action of BF-175 in PCa and its efficacy in PCa remains fully elucidated.
METHOD: Prostate Oncomine and cBioportal databases contain prostate cancer patient datasets, which were queried for SREBP mRNA overexpression and copy number alterations. We used 4 PCa cell lines, namely PC3, PC3M, LNCaP, and C4-2B, to conduct our cell viability and proliferation assays, clonogenic survival assay, wound healing assay, trans-well migration, and invasion assays. RESULTS: SREBP inhibition by BF175 significantly reduced cell viability, proliferation, and clonogenic survival in all prostate cancer cell lines tested. Analysis of wound healing, trans-well migration, and invasion assay revealed that BF175 significantly reduced migration and invasion in all PCa cells tested. We also confirmed that BF175 inhibited the expression of SREBPs in the tested prostate cancer cell lines. Of note, BF175 exhibited significantly higher potency as an anticancer agent in more invasive prostate cancer cell lines than their less invasive counterparts.
CONCLUSION: Our results demonstrate that BF175 shows promise as a novel anticancer agent that may improve outcomes in lethal metastatic PCa.