<p>Fatostatin in Combination with Tamoxifen Induces Synergistic Inhibition in ER-Positive Breast Cancer</p>

Abstract

Background: Tamoxifen is the cornerstone of adjuvant therapy for hormone receptorpositive breast cancer. Despite its efficacy, limited drug sensitivity and endocrine resistance remain the important clinical challenges. The main objective of this study was to investigate fatostatin, which was found to sensitize breast cancer to the antitumour effect of tamoxifen both in vitro and in vivo. Methods: Fatostatin-induced ER degradation was detected by immunoprecipitation assay. The antitumour effect of fatostatin and tamoxifen on MCF-7 and T47D cells was assessed by MTT and colony forming assays. Cell cycle arrest was detected by flow cytometric analysis. Apoptosis was detected by annexin V/propidium iodide double staining and TUNEL assay. Autophagy was detected by MDC assay and acridine orange staining. Migration and invasion assays were performed using a Transwell system, and the efficacy of the synergistic use of fatostatin and tamoxifen in vivo was evaluated using an MCF-7 xenograft model in BALB/c nu/nu female mice. Results: The synergistic use of fatostatin and tamoxifen significantly suppressed cell viability and invasion, induced cell cycle arrest, and regulated apoptosis and autophagy in MCF-7 and T47D cell lines via PI3K-AKT-mTOR signalling. Additionally, the expression levels of Atg7/12/13, beclin and LC3B increased while p-mTOR and P62 expression levels decreased after treatment with fatostatin and tamoxifen. Tumor growth in the xenograft model was suppressed significantly with the synergistic treatment of fatostatin and tamoxifen. Conclusion: Fatostatin could induce ER degradation by K48-linked polyubiquitination, which was the key mechanism contributing to tamoxifen inhibition of PI3K-AKT-mTOR signalling in breast cancer. Fatostatin may have a promising clinical use for ER-positive breast cancer patients.

Targeting SREBP-1-Mediated Lipogenesis as Potential Strategies for Cancer

“…In pancreatic cancer, both fatostatin and PF429242 inhibit cell proliferation and the growth of xenograft tumor by reducing SREBP-1 and its downstream signaling cascades, such as FASN and SCD-1 ( 17 ). Additionally, the combination of fatostatin with tamoxifen has a synergistic effect on the inhibition of PI3K/Akt/mTOR signaling in ER-positive breast cancer ( 140 ). Together, fatostatin mainly regulates the activation of SREBP-1/2 to block different cancer progressions, while it also regulates the accumulations of PUFAs and the PI3K/Akt/mTOR pathway.…”

Cholesterol Metabolic Reprogramming in Cancer and Its Pharmacological Modulation as Therapeutic Strategy

“…The xenograft volume decreased after treatment with fatostatin ( 153 ). Moreover, the combined treatment with tamoxifen resulted synergic in reducing both in vitro cell proliferation and in vivo tumor growth in breast cancer ( 154 ).…”

Visualization and quantification of de novo lipogenesis using a FASN-2A-GLuc mouse model

“…Previous results showed that fatostatin could inhibit SREBPs, which are master transcriptional factors that regulate DNL ( 26 ). Previous findings also showed that fatostatin could reduce the weight of ob/ob mice and possesses high antitumor properties against various cancers ( 27 , 28 ). Using our reporter mouse model, we monitored the role of fatostatin in DNL induced by high glucose and fructose water.…”