Retracted: Lovastatin Inhibits RhoA to Suppress Canonical Wnt/β-Catenin Signaling and Alternative Wnt-YAP/TAZ Signaling in Colon Cancer

Abstract

Statins are first-line drugs used to control patient lipid levels, but there is recent evidence that statin treatment can lower colorectal cancer (CRC) incidence by 50% and prolong CRC patient survival through mechanisms that are poorly understood. In this study, we found that the treatment of APCmin mice by the mevalonate pathway inhibitor lovastatin significantly reduced the number of colonic masses and improved hypersplenism and peripheral anemia. Furthermore, reverse transcription polymerase chain reaction (RT-PCR) analysis of colonic mass tissues showed a potent inhibitory effect in both Wnt/β-catenin signaling and YAP/TAZ signaling in the lovastatin treatment group. The results of our transcriptomic analyses in RKO indicated that lovastatin regulated several proliferation-related signaling pathways. Moreover, lovastatin suppressed important genes and proteins related to the canonical Wnt/β-catenin and alternative Wnt-YAP/TAZ signaling pathways in RKO and SW480 cells, and these effects were rescued by mevalonic acid (MVA), as confirmed through a series of Western blotting, RT-PCR, and reporter assays. Given that statins suppress oncogenic processes primarily through the inhibition of Rho GTPase in the mevalonate pathway, we speculate that lovastatin can inhibit certain Rho GTPases to suppress both canonical Wnt/β-catenin signaling and alternative Wnt-YAP/TAZ signaling. In RKO cells, lovastatin showed similar inhibitory properties as the RhoA inhibitor CCG1423, being able to inhibit β-catenin, TAZ, and p-LATS1 protein activity. Our results revealed that lovastatin inhibited RhoA activity, thereby suppressing the downstream canonical Wnt/β-catenin and alternative Wnt-YAP/TAZ pathways in colon cancer cells. These inhibitory properties suggest the promise of statins as a treatment for CRC. Altogether, the present findings support the potential clinical use of statins in non-cardiovascular contexts and highlight novel targets for anticancer treatments.

Lipid metabolism reprogramming in colorectal cancer

“…Statins are the main agents used to control lipid levels and there is now evidence that lovastatin by mediating CRC progression through inhibition of Wnt/β‐catenin and YAP/TAZ is effective in 50% of CRC patients 90 . In addition, statins significantly reduced the activity of HMG‐CoA reductase in the mevalonate pathway, which is a key enzyme in cholesterol synthesis 91 .…”

“…Therefore, the mevalonate pathway would be expected to be an effective target for cancer therapy. Lovastatin has now been shown to inhibit metastasis and induce apoptosis 90 . In conclusion, we identified lovastatin as an inhibitor of CRC and thoroughly examined the potential mechanisms to compensate for the single action of statins, which were used only for lipid lowering in the past.…”

Inhibition of colorectal cancer tumorigenesis by ursolic acid and doxorubicin is mediated by targeting the Akt signaling pathway and activating the Hippo signaling pathway

“…Mst1/2 downregulation in the intestinal epithelium has been shown to induce activation of Yap, and may contribute to tumor proliferation and metastasis (53). Moreover, the overall and disease-free survival rates of patients with CRC with Yap upregulation have been shown to be markedly decreased (54,55). There is accumulating evidence that shows that the PI3K/Akt/mTOR signaling pathway is a key survival pathway that is unconventionally activated in numerous types of malignant tumor, including CRC (56,57).…”

Mutant p53, the Mevalonate Pathway and the Tumor Microenvironment Regulate Tumor Response to Statin Therapy

“…Geranylgeranyl-PP promotes nuclear localization and transcriptional activity of YAP/TAZ to drive cellular metabolism [ 45 , 47 ]. The inhibition of the MVA pathway reduces YAP/TAZ nuclear localization and induction of transcription [ 45 , 48 ]. In opposition to the inhibitory influence of the Hippo pathway, the Rho family of GTPases activate YAP/TAZ [ 49 ] and facilitate YAP/TAZ activation induced by a number of G-protein-coupled receptors [ 50 ].…”