Curcumin reverses oxaliplatin resistance in human colorectal cancer via regulation of TGF-β/Smad2/3 signaling pathway

Jiahuan Yin,1,* Li Wang,2,* Yong Wang,1 Hailong Shen,1 Xiaojie Wang,1 Lei Wu11Department of General Surgery, Shanghai Luodian Hospital, Shanghai 201908, People’s Republic of China; 2Department of Gynaecology and Obstetrics, Shanghai Luodian Hospital, Shanghai 201908, People’s Republic of China*These authors contributed equally to this workBackground: Oxaliplatin (OXA) resistance is a main obstacle to the chemotherapy of colorectal cancer (CRC). Epithelial-mesenchymal transition (EMT), which is mainly regulated by TGF-β/Smad signaling pathway, has gradually been recognized as an important mechanism for tumor chemoresistance. Studies have shown that curcumin regulated EMT processes in many human cancers. However, whether curcumin could regulate OXA resistance in CRC through modulating TGF-β/Smad signaling-mediated EMT remains unclear.Methods: In an attempt to investigate the effect of curcumin on OXA resistance in CRC, OXA-resistant cell line HCT116/OXA was established firstly. The effect of curcumin on cell proliferation was evaluated by MTT assay and Ki67 immunofluorescence staining, respectively. Cell apoptosis was evaluated by flow cytometry. In addition, transwell assay was used to detect the effect of curcumin on cell invasion and the activation of TGF-β/Smad signaling was examined by immunofluorescence and Western blot. Moreover, the therapeutic potential of curcumin was further examined in vivo using a CRC animal model.Results: The OXA-resistant cell line HCT116/OXA was successfully established, and combination of OXA with curcumin reduced OXA resistance in vitro. Besides, the combination treatment inhibited the expressions of p-p65 and Bcl-2, but increased the level of active-caspase3. In addition, curcumin inhibited EMT via regulation of TGF-β/Smad2/3 signaling pathway. Moreover, in vivo study confirmed curcumin could reverse OXA resistance in CRC.Conclusion: Our study indicated that curcumin could reserve OXA resistance in CRC through dampening TGF-β/Smads signaling in vitro and in vivo.Keywords: colorectal cancer, oxaliplatin resistance, curcumin, epithelial-mesenchymal transition, TGF-β/Smad signaling pathwa