Direct inhibition of the TLR4/MyD88 pathway by geniposide suppresses HIF‐1α‐independent VEGF expression and angiogenesis in hepatocellular carcinoma

Abstract

Background and Purpose: As a typical hypervascular tumour, hepatocellular carcinoma (HCC) is predominantly grown through angiogenesis. Geniposide is a promising anti-inflammatory compound found in Gardenia jasminoides, but its effects on the progression of HCC remain untested. Experimental Approach: The anti-HCC effects of geniposide was investigated in cellular models and orthotopic HCC mice. Transcriptional regulation of the VEGF promoter was measured by dual-luciferase reporter assay. The anti-angiogenic action of geniposide was measured by tube formation assay. Both surface plasmon resonance techniques and human phospho-kinase array analysis were utilized to validate the relationship between targets of geniposide and hepatocarcinogenesis. Key Results: Geniposide exhibited significant disruption of HCC proliferation, invasion, angiogenesis and lung metastasis in orthotopic HCC mice. Geniposide inhibited secretion of VEGF by HCC and suppressed the migration of endothelial cells and the formation of intra-tumour blood vessels, without cytotoxicity and independently of the transcription factor HIF-1α. Direct inhibition of TLR4 by geniposide led to the shutdown of the TLR4/MyD88 pathway and STAT3/Sp1-dependent VEGF production. However, LPS, an agonist of TLR4, restored STAT3/Sp1-related VEGF production in geniposide-inhibited HCC angiogenesis. Conclusion and Implications: The direct inhibitory effect of geniposide on TLR4/ MyD88 activation contributes to the suppression of STAT3/Sp1-dependent VEGF overexpression in HCC angiogenesis and pulmonary metastasis. This action of geniposide was not affected by stabilization of HIF-1α. Our study offers a novel anti-VEGF mechanism for the inhibition of HCC.

Virtual Screening of Natural Products against Type II Transmembrane Serine Protease (TMPRSS2), the Priming Agent of Coronavirus 2 (SARS-CoV-2)

“…This compound has the IUPAC name methyl (1S,4aS,7aS)-7-(hydroxymethyl)-1-[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-4-carboxylate and the common name geniposide and is one of the major iridoid glycosides of gardenia fruit. It was previously shown to inhibit 5-lipoxygenase [33] and the tumor-promoting factor P-glycoprotein [34] and have anti-angiogenic activity [35] and potential antiasthma properties [36]. Additionally, geniposide was shown recently to protect against sepsis-induced myocardial dysfunction by activating AMPKα to suppress myocardial reactive oxygen species (ROS) accumulation [37].…”

Geniposide inhibits proliferation and induces apoptosis of diffuse large B-cell lymphoma cells by inactivating the HCP5/miR-27b-3p/MET axis

“…Geniposide protects against lipid accumulation by decreasing oxidative stress and inflammation in non-alcohol fatty liver disease (NAFLD) [33]. The antitumor effect of geniposide has been indicated in several types of human cancers [6][7][8][9][10]. In our study, we first reported that geniposide acted as a tumor-suppressive factor in DLBCL cells by inhibiting cell proliferation and inducing apoptosis.…”

“…For example, geniposide alleviates NAFLD by modulating the Nrf2/AMPK/mTOR signaling pathway [33]. The TLR4/MyD88/NF-κB pathway is regulated by geniposide in several human diseases, such as diabetic cognitive impairment [34], acute liver injury [35], and HCC [7]. Moreover, miR-21 [36], miR-373 [37], miR-214 [38] and miR-224 [8] are under the regulation of geniposide.…”

“…For example, geniposide treatment exerts an antiproliferative effect on an oral squamous carcinoma cell line (HSC-3) in vitro [6]. Geniposide inhibits the proliferation, migration, and invasion potentials of hepatocellular carcinoma (HCC) cells and induces apoptosis [7,8]. In gastric cancer (GC), geniposide treatment also has inhibitory effects on the malignant biological behaviors of cancer cells [9].…”

Intestinal Absorption of Geniposide and Inhibition of Transporter-P-GP Across the Caco-2 Monolayer

“…Geniposide (GE), an iridoid glycoside compound, is the major active component of Gardenia jasminoides Ellis fruit, which is traditionally used for its antiphlogistic and antipyretic effects in many Asian countries [1] . In recent years, the pharmacological effects of geniposide on antioxidation and angiogenesis have been gradually studied [2,3] . The development of new drugs and the wide application of drugs and herbs resulted in the potential of drug-drug interaction (DDI) have been noticed [4] .…”