Targeting STAT3 with SH-4-54 suppresses stemness and chemoresistance in cancer stem-like cells derived from colorectal cancer

BACKGROUND Over the years, the numbers of treatment options for colorectal cancer (CRC) have increased, leading to notable improvements in the overall survival of CRC patients. Although therapy may initially yield positive results, the development of drug resistance can result in treatment failure and cancer recurrence. This resistance is often attributed to the presence of cancer stem cells (CSCs). These CSCs not only contribute to therapeutic resistance but also play crucial roles in the initiation and development of tumor metastasis. AIM To investigate the antitumor effects of SH-4-54, which are mediated by targeting CSCs relative to treatment outcomes. METHODS CSCs were enriched by culturing CRC cells in serum-free medium. Hallmarks of stemness and IL-6/JAK2/STAT3 signaling were detected by Western blotting. Indicators of CSC malignancy, including proliferation, invasion, and tumor formation, were measured. RESULTS In this study, we employed SH-4-54, which exhibits anticancer activity in solid tumors through targeting the SH2 domain of both the signal transducer and activator of transcription (STAT)3 and the STAT5, and evaluated its effects on stemness and chemoresistance in colorectal CSCs. As expected, SH-4-54 treatment inhibited the phosphorylation of STAT3 (p-STAT3) and decreased the percentage of ALDH1A1-positive CRC cells. The addition of SH-4-54 dissociated colorectal spheroids and decreased the expression of stemness markers, including ALDH1A1, CD44 and Nanog. SH-4-54 treatment decreased IL-6/JAK2/STAT3 signaling by inhibiting p-STAT3 and thus inhibited spheroid formation by SW480 and LoVo cells. Moreover, SH-4-54 treatment inhibited indicators of malignancy, including cell proliferation, invasion, and tumor formation, in CSCs in vitro and in vivo. Notably, SH-4-54 treatment significantly increased chemosensitivity to oxaplatin. CONCLUSION Taken together, these results indicate that SH-4-54 is a promising molecule that exerts antitumor effects on colorectal CSCs by inhibiting STAT3 signaling.