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.