Fatostatin reverses progesterone resistance by inhibiting the SREBP1-NF-κB pathway in endometrial carcinoma

Abstract

Progesterone resistance can significantly restrict the efficacy of conservative treatment for patients with endometrial cancer who wish to preserve their fertility or those who suffer from advanced and recurrent cancer. SREBP1 is known to be involved in the occurrence and progression of endometrial cancer, although the precise mechanism involved remains unclear. In the present study, we carried out microarray analysis in progesterone-sensitive and progesterone-resistant cell lines and demonstrated that SREBP1 is related to progesterone resistance. Furthermore, we verified that SREBP1 is over-expressed in both drug-resistant tissues and cells. Functional studies further demonstrated that the inhibition of SREBP1 restored the sensitivity of endometrial cancer to progesterone both in vitro and in vivo, and that the over-expression of SREBP1 promoted resistance to progesterone. With regards to the mechanism involved, we found that SREBP1 promoted the proliferation of endometrial cancer cells and inhibited their apoptosis by activating the NF-κB pathway. To solve the problem of clinical application, we found that Fatostatin, an inhibitor of SREBP1, could increase the sensitivity of endometrial cancer to progesterone and reverse progesterone resistance by inhibiting SREBP1 both in vitro and in vivo. Our results highlight the important role of SREBP1 in progesterone resistance and suggest that the use of Fatostatin to target SREBP1 may represent a new method to solve progesterone resistance in patients with endometrial cancer.

A Novel Small-Molecule Inhibitor of SREBP-1 Based on Natural Product Monomers Upregulates the Sensitivity of Lung Squamous Cell Carcinoma Cells to Antitumor Drugs

“…SREBP-1 is a transcription factor bound to the sterol regulatory elements (SREs) located in the promoters of its target genes involved in fatty acid and triglyceride synthesis ( Hagen et al, 2010 ; Galbraith et al, 2018 ). Increasing evidence indicate that inhibition of SREBP-1’s activation not only decreases synthesis of fat and impedes glucose uptake of cancerous cells but also enhances the sensitivity of cells to antitumor agents ( Zhou et al, 2019 ; Chen et al, 2021 ; Ma et al, 2021 ). Although SREBP-1 is therefore an intervention target for anti-tumor therapy, current studies on small molecule inhibitors of SREBP-1 are limited.…”

Mesencephalic astrocyte‐derived neurotrophic factor alleviates non‐alcoholic steatohepatitis induced by Western diet in mice

“…In the present study, knocking down MANF in primary cultures markedly upregulated SREBP1 and LIPIN1 at the levels of mRNA (Figure 4A) and protein (Figure 4B,C), consistent with results in LKO mice (Figure 1). Knocking down MANF also significantly increased lipid accumulation in primary hepatocytes, which was partially reversed by the specific SREBP1 inhibitor fatostatin 34 (Figure 4D). Conversely, overexpressing MANF downregulated SREBP1 and LIPIN1 at the level of mRNA (Figure 4E) and protein (Figure 4F,G).…”

Inhibition of SREBP-1 Activation by a Novel Small-Molecule Inhibitor Enhances the Sensitivity of Hepatocellular Carcinoma Tissue to Radiofrequency Ablation

“…Betulin can exert anti-tumor activity in HCC (78)(79)(80). Pseudoprotodioscin and Fatostatin have been less studied in HCC, but it has also been clearly reported in other tumor types (81)(82)(83)(84).…”