Pharmacologic Inhibition of SIRT1 Limits the Growth of Tumoral and Metastatic Granulosa Cells by Affecting mTOR, Myc, and E2F Pathways

Abstract

Clinical management of patients with ovarian granulosa cell tumor (GCT) remains poor. Sirtuin-1 (SIRT1), a deacetylase enzyme involved in the regulation of tumor growth and metastasis, may represent a therapeutic target because of the availability of selective pharmacologic inhibitors with minimal toxicity. We assessed the possible overexpression of SIRT1 during tumorigenesis by Western blotting and IHC. We tested the effects of SIRT1 inhibition by EX-527 on growth, proliferation, death, migration, metabolism, and gene expression by RNA sequencing in vitro on three GCT cell lines (AT29, KGN, and COV434). Tumor growth in response to EX-527 treatment was examined in nude mice carrying subcutaneous GCT cell grafts using an electronic caliper and in GCT of AT83 mice by three-dimensional ultrasound imaging system. SIRT1 abundance increased during tumorigenesis. In vitro treatment with EX-527 efficiently reduced cell growth, either by inducing apoptosis or by inhibiting proliferation. EX-527 induced alterations in mTOR-, Myc-, and E2F-driven pathways, and in those controlling cell metabolism and oxidative stress. The administration of this treatment for 4 weeks efficiently reduced tumor progression in vivo. Inhibition of SIRT1 activity may have GCT growth suppressive effects, providing a rationale for evaluating the therapeutic potential of drugs targeting SIRT1 in patients.