High-grade serous ovarian cancer (HGSOC) is one of the deadliest cancers for women, with a low survival rate, no early detection biomarkers, a high rate of recurrence, and few therapeutic options. Forskolin, an activator of cyclic AMP signaling, has several anticancer activities, including against HGSOC, but has limited use in vivo. Its water-soluble derivative, colforsin daropate, has the same mechanism of action as forskolin and is used to treat acute heart failure. Here, we investigated the potential of colforsin daropate as a treatment for HGSOC. We found that colforsin daropate induced cell cycle arrest and apoptosis in cultured HGSOC cells and spheroids but had negligible cytotoxicity in immortalized, nontumorigenic fallopian tube secretory cells and ovarian surface epithelial cells. Colforsin daropate also prevented HGSOC cells from invading ovarian surface epithelial cell layers in culture. In vivo, colforsin daropate reduced tumor growth, synergized with cisplatin (a standard chemotherapy in ovarian cancer care), and improved host survival in subcutaneous and intraperitoneal xenograft models. These antitumor effects of colforsin daropate were mediated in part by its reduction in the abundance and transcriptional activity of the oncoprotein c-MYC, which is often increased in HGSOC. Our findings demonstrate that colforsin daropate may be a promising therapeutic that could be combined with conventional therapies to treat HGSOC.

2022-06-01·Redox biology1区 · 生物学

Glia maturation factor-β induces ferroptosis by impairing chaperone-mediated autophagic degradation of ACSL4 in early diabetic retinopathy

1区 · 生物学

ArticleOA

作者: Liu, Caiying ; Wang, Juan ; Shi, Si ; Sun, Wan ; Gao, Furong ; Zhang, Jingfa ; Lu, Lixia ; Li, Jiao ; Zhu, Tong ; Xu, Guo-Tong ; Jin, Caixia ; Tian, Haibin ; Ou, Qingjian ; Zhang, Jieping ; Xu, Jing-Ying

Diabetic retinopathy (DR) is one of the leading causes of blindness in the world, and timely prevention and treatment are very important. Previously, we found that a neurodegenerative factor, Glia maturation factor-β (GMFB), was upregulated in the vitreous at a very early stage of diabetes, which may play an important role in pathogenesis. Here, we found that in a high glucose environment, large amounts of GMFB protein can be secreted in the vitreous, which translocates the ATPase ATP6V1A from the lysosome, preventing its assembly and alkalinizing the lysosome in the retinal pigment epithelial (RPE) cells. ACSL4 protein can be recognized by HSC70, the receptor for chaperone-mediated autophagy, and finally digested in the lysosome. Abnormalities in the autophagy-lysosome degradation process lead to its accumulation, which catalyzes the production of lethal lipid species and finally induces ferroptosis in RPE cells. GMFB antibody, lysosome activator NKH477, CMA activator QX77, and ferroptosis inhibitor Liproxstatin-1 were all effective in preventing early diabetic retinopathy and maintaining normal visual function, which has powerful clinical application value. Our research broadens the understanding of the relationship between autophagy and ferroptosis and provides a new therapeutic target for the treatment of DR.

2020-09-01·European review for medical and pharmacological sciences

MicroRNA-362 inhibits cell growth and metastasis in glioblastoma by targeting MAPK1.

Article

作者: Shi, H-Z ; Zhu, H ; Wang, D-N ; Ma, L-N

OBJECTIVE:

Glioblastoma (GBM) is a deadly brain cancer that seriously threatens the lives of patients. Moreover, various microRNAs (miRNAs) have been found to be involved in the progression of GBM. The purpose of this study is to preliminarily elucidate the regulatory mechanism of miR-362 in GBM.

PATIENTS AND METHODS:

The abnormal expression of miR-362 and MAPK1 was detected by RT-qPCR or Western blot analysis in GBM tissues and cells. CCK-8 and transwell assays were performed to measure cell proliferation, migration and invasion. The relationship between miR-362 and MAPK1 was confirmed by luciferase reporter assay.

RESULTS:

MiR-362 expression was reduced in GBM tissues and cells. The decreased expression of miR-362 predicted poor prognosis in GBM patients. Functionally, overexpression of miR-362 inhibited the proliferation and metastasis of GBM cells. In addition, miR-362 directly targets MAPK1. MAPK1 was negatively correlated with miR-362 expression in GBM. Moreover, MAPK1 was upregulated and served as a tumor promoter in GBM. More importantly, the upregulation of MAPK1 weakened the inhibitory effect of miR-362 on cell proliferation and metastasis in GBM.

CONCLUSIONS:

MiR-362 restrains cell proliferation and metastasis in GBM by targeting MAPK1, indicating that miR-362 functions as a tumor suppressor in GBM.

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