TY - JOUR AB - Signal transducer and activator of transcription 3 (STAT3) activation is associated with drug resistance induced by anti‑epidermal growth factor receptor (anti‑EGFR) therapy in the treatment of colon cancer. Thus, the combined inhibition of EGFR and STAT3 may prove beneficial for this type of cancer. STAT3 has been proven to play a critical role in colon cancer initiation and progression, and is considered the primary downstream effector driven by interleukin‑6 (IL‑6). A disintegrin and metalloproteinase 17 (ADAM17), documented as an oncogene, catalyzes the cleavage of both EGF and IL‑6R, inducing EGFR signaling and enabling IL‑6 trans‑signaling to activate STAT3 in a wide range of cell types to promote inflammation and cancer development. As a natural product, shikonin (SKN) has been found to function as an antitumor agent; however, its role in the regulation of ADAM17 and IL‑6/STAT3 signaling in colon cancer cells remains unknown. In the present study, it was found that SKN inhibited colon cancer cell growth, suppressed both constitutive and IL‑6‑induced STAT3 phosphorylation, and downregulated the expression of ADAM17. ADAM17 expression was not altered in response to STAT3 knockdown, while IL‑6‑induced STAT3 activation did not induce ADAM17 transcripts. Furthermore, it was demonstrated that SKN did not affect the expression of key proteins involved in the maturation and degradation of ADAM17. SKN decreased ADAM17 expression possibly through reactive oxygen species (ROS)‑mediated translational inhibition, as evidenced by the increased ADAM17 mRNA and phosphorylation levels of eukaryotic initiation factor 2α (eIF2α). The expression of ADAM17 and p‑eIF2α was reversed by N‑acetylcysteine (NAC, a ROS scavenger). Taken together, these results indicate that the concurrent inhibition of ADAM17 and IL‑6/STAT3 signaling by SKN may synergistically contribute to the suppression of colon cancer cell growth. AD - Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China AU - Shi,Wei AU - Men,Lintong AU - Pi,Xiu AU - Jiang,Tao AU - Peng,Dewei AU - Huo,Shengqi AU - Luo,Pengcheng AU - Wang,Moran AU - Guo,Junyi AU - Jiang,Yue AU - Peng,Lulu AU - Lin,Li AU - Li,Sheng AU - Lv,Jiagao DA - 2021/12/01 DO - 10.3892/ijo.2021.5279 IS - 6 JO - Int J Oncol KW - A disintegrin and metalloproteinase 17 IL‑6 STAT3 colon cancer shikonin PY - 2021 SN - 1019-6439 1791-2423 SP - 99 ST - Shikonin suppresses colon cancer cell growth and exerts synergistic effects by regulating ADAM17 and the IL‑6/STAT3 signaling pathway T2 - International Journal of Oncology TI - Shikonin suppresses colon cancer cell growth and exerts synergistic effects by regulating ADAM17 and the IL‑6/STAT3 signaling pathway UR - https://doi.org/10.3892/ijo.2021.5279 VL - 59 ER -