Abstract
BackgroundRetinoid X receptor-alpha (RXRα) is a key member of the nuclear receptor superfamily. We recently demonstrated that proteolytic cleavage of RXRα resulted in production of a truncated product, tRXRα, which promotes cancer cell survival by activating phosphatidylinositol-3-OH kinase (PI3K)/AKT pathway. However, how the tRXRα-mediated signaling pathway in cancer cells is regulated remains elusive.Methodology/Principal FindingsWe screened a natural product library for tRXRα targeting leads and identified that triptolide, an active component isolated from traditional Chinese herb Trypterygium wilfordii Hook F, could modulate tRXRα-mediated cancer cell survival pathway in vitro and in animals. Our results reveal that triptolide strongly induces cancer cell apoptosis dependent on intracellular tRXRα expression levels, demonstrating that tRXRα serves as an important intracellular target of triptolide. We show that triptolide selectively induces tRXRα degradation and inhibits tRXRα-dependent AKT activity without affecting the full-length RXRα. Interestingly, such effects of triptolide are due to its activation of p38. Although triptolide also activates Erk1/2 and MAPK pathways, the effects of triptolide on tRXRα degradation and AKT activity are only reversed by p38 siRNA and p38 inhibitor. In addition, the p38 inhibitor potently inhibits tRXRα interaction with p85α leading to AKT inactivation. Our results demonstrate an interesting novel signaling interplay between p38 and AKT through tRXRα mediation. We finally show that targeting tRXRα by triptolide strongly activates TNFα death signaling and enhances the anticancer activity of other chemotherapiesConclusions/SignificanceOur results identify triptolide as a new xenobiotic regulator of the tRXRα-dependent survival pathway and provide new insight into the mechanism by which triptolide acts to induce apoptosis of cancer cells. Triptolide represents one of the most promising therapeutic leads of natural products of traditional Chinese medicine with unfortunate side-effects. Our findings will offer new strategies to develop improved triptolide analogs for cancer therapy.
Highlights
Retinoid X receptor-a (RXRa) is a unique member of the nuclear receptor superfamily [1,2]
Our results show that triptolide strongly induces cancer cell apoptosis by regulating tRXRa expression and function
When the apoptotic effect of triptolide was examined, we found that the levels of tRXRa expression in these cancer cell lines were associated with their responses to the killing effect of triptolide
Summary
Retinoid X receptor-a (RXRa) is a unique member of the nuclear receptor superfamily [1,2]. In addition to reduced levels of RXRa protein, altered RXRa function by phosphorylation is associated with the development of human hepatocellular carcinoma [9,10,11] and colon cancer [12]. Altered RXRa function can be resulted from its proteolytic cleavage of the receptor protein, which is frequently observed in various human tumors [15,16,17,18]. TRXRa acquires new function that is different from RXRa. Since tRXRa is often elevated in cancer cells, it is expected that targeting tRXRa represents a more effective and specific strategy for developing RXR-based anticancer drug. We recently demonstrated that proteolytic cleavage of RXRa resulted in production of a truncated product, tRXRa, which promotes cancer cell survival by activating phosphatidylinositol-3-OH kinase (PI3K)/AKT pathway. How the tRXRa-mediated signaling pathway in cancer cells is regulated remains elusive
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