Abstract
BackgroundColorectal cancer (CRC) is the second deadliest malignant disease in the world and the leukemia inhibitory factor receptor/signal transducers and activators of transcriptions (LIFR/STATs) signaling axis plays an important role in the molecular biology of CRC.MethodsCell function tests were performed to observe the inhibitory effect of cynaropicrin on human CRC cells (RKO, HCT116, and DLD-1). Expression levels of LIFR, P-STAT3, P-STAT4, and apoptotic proteins were detected by Western blotting. Immunoprecipitation confirmed the presence of LIFR/STAT3/STAT4 complex. Cell immunofluorescence assay was used to observe the subcellular localization of STAT3 and STAT4. In vivo efficacy of cynaropicrin was evaluated by a xenotransplantation model in nude mice.ResultsCynaropicrin significantly reduced the survival ability of human CRC cells and promoted apoptosis in a dose-dependent manner. Western blotting results suggested that the antitumor effects of cynaropicrin might be mediated by inhibition of the LIFR/STATs axis. Cynaropicrin reduced the formation of STAT3/STAT4 heterodimers and blocked their entry into the nucleus. Cynaropicrin also suppressed tumor growth in the xenograft model.ConclusionThe results showed that cynaropicrin exerted a strong inhibitory effect on CRC in vitro and in vivo. Our study concluded that cynaropicrin has potential application prospects in the field of anti-CRC therapy.
Highlights
Colorectal cancer (CRC), one of the most prevalent malignant diseases, ranks second among all cancers in terms of mortality and third in terms of incidence worldwide (Bray et al, 2018)
These data suggested that cynaropicrin can effectively inhibit the growth and proliferation of human CRC cells
Via detecting the protein expression level by Western blotting, it was found that treatment with cynaropicrin obviously controlled the level of phosphorylate-STAT3 in HCT116, RKO, and DLD-1 cells in a time- and dose-dependent manner (Figures 4A,B). These findings proved that cynaropicrin induced CRC cell death mainly through the STAT3 pathway
Summary
Colorectal cancer (CRC), one of the most prevalent malignant diseases, ranks second among all cancers in terms of mortality and third in terms of incidence worldwide (Bray et al, 2018). Leukemia inhibitory factor (LIF) is a member of the interleukin-6 (IL-6) family and has the most multi-potent action. LIF binds to leukemia inhibitory factor receptor (LIFR) with high affinity (Boulanger et al, 2003), activating the Janus Kinase (JAK) family of tyrosine kinases, JAK1 (Ernst et al, 1996). The STAT protein is activated to form a signal-enhanced dimer that enters the nucleus and upregulates the transcription of the corresponding cytokine response genes (Zhao et al, 2020). Colorectal cancer (CRC) is the second deadliest malignant disease in the world and the leukemia inhibitory factor receptor/signal transducers and activators of transcriptions (LIFR/STATs) signaling axis plays an important role in the molecular biology of CRC
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