Garcinone C Suppresses Tumorsphere Formation and Invasiveness by Hedgehog/Gli1 Signaling in Colorectal Cancer Stem-like Cells

Abstract

Hyperactivation of hedgehog signaling occurs in colorectal cancer stem-like cells (CSCs), a rare subpopulation, potentially involved in metastasis, chemotherapy resistance, and cancer relapse. Garcinone C, a xanthone isolated from mangosteen (Garcinia mangostana), suppresses colorectal cancer in vivo and in vitro by inhibiting Gli1-dependent noncanonical hedgehog signaling. Herein, we investigated the effect of garcinone C on cancer stemness and invasiveness in colorectal cancer; Gli1 was noted as pivotal in maintaining stemness and invasiveness in HCT116 and HT29 CSCs. Garcinone C inhibited the proliferation and selfrenewal of HCT116 and HT29 CSCs. Colon cancer stemness markers such as CD44, CD133, ALDH1, and Nanog were significantly decreased by garcinone C. Computational studies showed that garcinone C showed a high affinity with the Gli1 protein ZF domain by forming hydrogen bonds with amino acid residues of ASP244, ARG223, and ASP216. Besides, MG132 blocked the effects of garcinone C on Gli1. Thus, garcinone C suppressed colorectal CSCs by binding to Gli1 and enhancing its degradation. MMP2 and MMP9 levels, invasive-related markers, were increased in HCT116 CSCs but decreased by garcinone C. E-cadherin level was reduced in HCT116 CSCs, while the presence of garcinone C was restored. Garcinone C inhibited the proliferation and invasiveness of colorectal CSCs by targeting Gli1-dependent Hh signaling. Garcinone C may be a potent natural agent against colorectal cancer relapse.

Garcinone C attenuates RANKL-induced osteoclast differentiation and oxidative stress by activating Nrf2/HO-1 and inhibiting the NF-kB signaling pathway

“…Mangosteen is known for its antioxidant [ 13 , 14 ], anti-inflammatory [ 15 ] and anticancer activities [ [16] , [17] , [18] ]. Gar C has recently been reported to have protective effects against rectal, colon and nasopharyngeal cancers [ [18] , [19] , [20] ]. Indeed, antitumor activity is closely related to antioxidant activity.…”

CD44 and its implication in neoplastic diseases

“…CD44 + CSCs is a more appreciated subset which plays key roles in conventional stemness‐related Hedgehog signaling activation. 212 , 213 In CD44 + HCC, suppressing Hedgehog signaling was reported to reverse sorafenib resistance. 77 On top of that, in patients with CRC, CD44‐high tumors have been shown to be enriched for the Wnt/β‐catenin and Hedgehog signaling pathways.…”

“…CD44 + CSCs is a more appreciated subset which plays key roles in conventional stemness‐related Hedgehog signaling activation 212,213 . In CD44 + HCC, suppressing Hedgehog signaling was reported to reverse sorafenib resistance 77 .…”