Withaferin A suppresses skin tumor promotion by inhibiting proteasome-dependent isocitrate dehydrogenase 1 degradation.
Transl Cancer Res
; 8(6): 2449-2460, 2019 Oct.
Article
in En
| MEDLINE
| ID: mdl-35116997
ABSTRACT
BACKGROUND:
The metabolic enzyme isocitrate dehydrogenase 1 (IDH1) belonging to ß-decarboxylase dehydrogenase family has been identified as a tumor suppressor. Withaferin A (WA), a bioactive compound derived from Withania somnifera, has the anti-tumor activity. Based on the data set that WA inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced IDH1 inactivation and mitochondrial dysfunction, we focused on how WA suppressed the skin carcinogenesis mediated by IDH1.METHODS:
The mRNA levels of IDH1 were measured after treated with TPA and/or WA. The expression of IDH1, lactate dehydrogenase (LDH) involved in glycolysis, hypoxia inducible factor-1α (HIF-1α) and its target gene glucose transporter-1 (Glut1) were detected. The activities of proteasome and the mitochondrial complex I related to mitochondrial functions were determined. The enzymatic activities of LDH, proline hydroxylase (PHD) and vascular endothelial growth factor (VEGF) were analyzed.RESULTS:
The qPCR data have shown the mRNA levels of IDH1 were no difference with TPA and/or WA treatment. Next, data demonstrated that WA could stabilize IDH1 by inhibiting the ubiquitin-proteasome pathway (UPP). Followed by illuminating the mechanism of IDH1 inhibiting tumorigenesis, the results mirrored that upregulated IDH1 suppressed LDH activity whereas increased mitochondrial complex I activity. Furthermore, via its product α-KG, upregulated IDH1 activated PHD, and inhibited HIF-1α and its downstream signaling pathway.CONCLUSIONS:
Our results indicate that WA inhibits tumor promotion partially via stabilizing IDH1, leading to inactivating the HIF-1α signaling.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Type of study:
Prognostic_studies
Language:
En
Journal:
Transl Cancer Res
Year:
2019
Document type:
Article
Affiliation country:
China