Celastrol Stimulates Hypoxia-Inducible Factor-1 Activity in Tumor Cells by Initiating the ROS/Akt/p70S6K Signaling Pathway and Enhancing Hypoxia-Inducible Factor-1α Protein Synthesis

Abstract

Celastrol, a tripterine derived from the traditional Chinese medicine plant Tripterygium wilfordii Hook F. (“Thunder of God Vine”), has been reported to have multiple effects, such as anti-inflammation, suppression of tumor angiogenesis, inhibition of tumor growth, induction of apoptosis and protection of cells against human neurodegenerative diseases. However, the mechanisms that underlie these functions are not well defined. In this study, we reported for the first time that Celastrol could induce HIF-1α protein accumulation in multiple cancer cell lines in an oxygen-independent manner and that the enhanced HIF-1α protein entered the nucleus and promoted the transcription of the HIF-1 target genes VEGF and Glut-1. Celastrol did not influence HIF-1α transcription. Instead, Celastrol induced the accumulation of the HIF-1α protein by inducing ROS and activating Akt/p70S6K signaling to promote HIF-1α translation. In addition, we found that the activation of Akt by Celastrol was transient. With increased exposure time, inhibition of Hsp90 chaperone function by Celastrol led to the subsequent depletion of the Akt protein and thus to the suppression of Akt activity. Moreover, in HepG2 cells, the accumulation of HIF-1α increased the expression of BNIP3, which induced autophagy. However, HIF-1α and BNIP3 did not influence the cytotoxicity of Celastrol because the main mechanism by which Celastrol kills cancer cells is through stimulating ROS-mediated JNK activation and inducing apoptosis. Furthermore, our data showed that the dose required for Celastrol to induce HIF-1α protein accumulation and enhance HIF-1α transcriptional activation was below its cytotoxic threshold. A cytotoxic dose of Celastrol for cancer cells did not display cytotoxicity in LO2 normal human liver cells, which indicated that the novel functions of Celastrol in regulating HIF-1 signaling and inducing autophagy might be used in new applications, such as in anti-inflammation and protection of cells against human neurodegenerative diseases. Future studies regarding these applications are required.

Inducible glomerular erythropoietin production in the adult kidney

“…There are, however, emerging findings suggesting that cellular HIF levels may also be regulated at normal oxygen tensions either by changes of HIF gene transcription, by endogenous modulation of PHD activity, or by endogenous modulation of HIF-protein degradation. [59][60][61][62][63][64] If and how those oxygen-independent modulations of cellular HIF-2 levels could be relevant for the glomerular endocrine switch from renin to EPO expression remains to be clarified. Another important aspect in this context that awaits clarification is whether the HIF-2-induced glomerular endocrine switch is reversible.…”

Effects of 17β-estradiol and 2-methoxyestradiol on the oxidative stress-hypoxia inducible factor-1 pathway in hypoxic pulmonary hypertensive rats

“…Hypoxia-inducible factor-1 (HIF-1), a master regulator of gene expression induced by hypoxia, serves an important role in the origin and development of HPH (9). A recent study has demonstrated that ROS serve an important role in the regulation of HIF-1 expression and activity (10).…”

Celastrol Induces Autophagy by Targeting AR/miR-101 in Prostate Cancer Cells

“…These results support the negative regulation of AR on celastrol-induced autophagy that was found in AR positive cells. It has been reported that celastrol induces autophagy in AR negative prostate cancer cell line such as PC-3 as well as other type of cancers such as pancreatic cancer and hepatocarcinoma [ 21 , 22 ]. Activation of HIF-1/BNIP3 has been proved to be a mechanism for celastrol to induce autophagy in those types of cells [ 22 ].…”