Ursolic acid inhibits the activation of smoothened‐independent non‐canonical hedgehog pathway in colorectal cancer by suppressing AKT signaling cascade

Abstract

It is being brought to light that smoothened (SMO)‐independent non‐canonical Hedgehog signaling is associated with the pathogenesis of various cancers. Ursolic acid (UA), a pentacyclic triterpenoid present in many medicinal herbs, manifests potent effectiveness against multiple malignancies including colorectal cancer (CRC). In our previous study, UA was found to protect against CRC in vitro by suppression of canonical Hedgehog signaling cascade. Here, the influence of UA on SMO‐independent non‐canonical Hedgehog signaling in CRC was investigated in the present study, which demonstrated that UA hampered the proliferation and migration, induced the apoptosis of HCT‐116hSMO− cells with SMO gene knockdown, accompanied by the augmented expression of the suppressor of fused (SUFU), and lessened levels of MYC (c‐Myc), glioma‐associated oncogene (GLI1) and Sonic Hedgehog (SHH), and lowered phosphorylation of protein kinase B (PKB, AKT), suggesting that UA diminished non‐canonical Hedgehog signal transduction in CRC. In HCT‐116hSMO− xenograft tumor, UA ameliorated the symptoms, impeded the growth and caused the apoptosis of CRC, with heightened SUFU expression, and abated levels of MYC, GLI1, and SHH, and mitigated phosphorylation of AKT, indicating that UA down‐regulated non‐canonical Hedgehog signaling cascade in CRC. Taken together, UA may alleviate CRC by suppressing AKT signaling‐dependent activation of SMO‐independent non‐canonical Hedgehog pathway.

Ursolic Acid Suppresses Colorectal Cancer by Down-Regulation of Wnt/β-Catenin Signaling Pathway Activity

“…Therefore, effects of UA on intestinal inflammation and the cross-talk between Wnt/β-catenin and inflammation merit intensive investigations. In addition, we previously certified that UA encumbers smoothened-independent non-canonical Hedgehog signaling of CRC . Moreover, UA is documented to simultaneously target multiple signaling, e.g., mammalian target of rapamycin/AKT, mitogen-activated protein kinase, and cyclooxygenase 2 pathways, to suppress CRC .…”

“…Phytochemicals including UA may exert powerful efficacy against a variety of malignancies, such as CRC, gastric cancer, breast cancer, prostate cancer, , and lung cancer, with fewer adverse reactions in comparison with the compounds of chemotherapy, which gives rise to broad utilization of phytochemicals as nutraceuticals for intervention in various cancers. However, the action mechanisms for most phytochemicals remain to be clarified, and UA is one of them in great need of exploration.…”

“…In addition, we previously certified that UA encumbers smoothened-independent non-canonical Hedgehog signaling of CRC. 18 Moreover, UA is documented to simultaneously target multiple signaling, e.g., mammalian target of rapamycin/AKT, mitogen-activated protein kinase, and cyclooxygenase 2 pathways, to suppress CRC. 39 Toward a thorough mechanistic understanding of how UA exerts anti-CRC potency, the impact of UA on the cross-talk among the Wnt signaling cascade and other signaling axes should be explored.…”

“…h i b i t e d .no.. The mouse CRC model of SW620 xenograft tumors was established as before 18. SW620 cells at 1 × 10 7 cells/mouse were subcutaneously implanted in the flank of nude mice, supplied by Speifu Biotechnology (Beijing, China).…”