Antroquinonol is to act as isoprenyltransferase inhibitor which indirectly blocks the prenylation of newly synthesized Ras and Ras-related GTPases superfamily proteins, leading to activation of autophagy and associated mode of cell death in cancer cells. The Ras/Rho-PI3K-Akt-mTOR pathway, which is associated with proliferation, motility, metabolism, and differentiation, is inhibited in response to Antroquinonol. Activating mutation of Ras oncogene was found in approximately one-third of all human cancers and up to 90% in pancreatic cancer.
Antroquinonol is the smallest anticancer molecule isolated from Antrodia camphorata thus far. The ubiquinone-like structure of Antroquinonol exhibits a broad spectrum of activity against malignancies in vivo and in vitro. The mechanism of action of Antroquinonol has been studied and revealed that Antroquinonol plays a role in the inhibition of Ras and Ras-related small GTP-binding protein functions through the inhibition of protein isoprenyl transferase activity in cancer cells.
Using cell line-based assays, we found that the inactive forms of Ras and Rho proteins were significantly elevated after treatment with Antroquinonol. We also demonstrated that Antroquinonol binds directly to farnesyltransferase and geranylgeranyltransferase-I, which are key enzymes involved in activation of
Ras-related proteins, and inhibits enzymes activities in vitro. Furthermore, a molecular docking analysis illustrated that the isoprenoid moiety of Antroquinonol binds along the hydrophobic cavity of farnesyltransferase similar to its natural substrate, farnesyl pyrophosphate. In contrast, the ring structure of Antroquinonol lies adjacent to the Ras-CAAX motif-binding site on farnesyltransferase.
The molecular docking study also showed a reasonable correlation with the IC50 values of Antroquinonol analogues. We also found that the levels of LC3B-II and the autophagosome-associated LC3 form were also significantly increased in H838 after Antroquinonol administration. In conclusion, Antroquinonol inhibited Ras and Ras-related GTP-binding protein activation through inhibition of protein isoprenyl
transferase activity, leading to activation of autophagy and associated mode of cell death in cancer cells.
Our previous studies revealed that Antroquinonol triggers antitumor activity through the inhibition of PI3K-Akt-mTOR pathway . Here, we provide evidence that Antroquinonol indirectly inhibits Ras and Rho processing through inhibition of
isoprenyltransferase activity. It has been observed that cooperation between Ras and Rho families of small GTPases are required for PI3K activation, which in accordance with our findings.
Thus, the possible signaling pathways that contribute to Antroquinonol-
mediated antitumor activity are summarized in the following figure. The Ras/Rho-PI3K-Akt-mTOR pathway, which is associated with proliferation, motility, metabolism, and differentiation, isinhibited in response to Antroquinonol. We believed that multiple signaling pathways are simultaneously involved in response to Antroquinonol stimulation. Thus, Antroquinonol may promote its anticancer effects by regulating cross talk in a complex signaling network that results in apoptosis and autophagy.
In summary, this is the first mechanism for the anticancer activity of Antroquinonol. Inhibition of isoprenyltransferase activity suppresses prenylation of multiple signaling molecules, interfering with downstream signaling.
Ras is a pivotal signaling protein in a complex network that regulates several aspects of normal cell growth and malignant transformation.Activating mutations in Ras, especially K-Ras, frequently occur in human cancers. Thus, targeting Ras is a promising strategy for treating cancer. Based on the biochemical characterization and molecular docking analysis in this study, Antroquinonol inhibits Ras and Rho processing via inhibition of the enzyme isoprenyltransferase activity, such as FTase and GGTase-I, ultimately resulting in cell death.
Antroquinonol is now undergoing Phase 2 clinical evaluation in patients with nonsmall cell lung cancer and pancreatic cancer and other indications.Understanding the mechanism of action of Antroquinonol will facilitate the identification of predictive biomarkers and will aid in the rational design of future clinical trials.
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