Targeting Skp2 by Tanshinone IIA overcomes chemoresistance in colorectal cancer

Fluorouracil (5-Fu)-based chemotherapy is a first-line treatment option for advanced colorectal cancer (CRC). However, long-term use of 5-Fu often leads to chemoresistance, which limits its therapeutic efficacy, highlighting the need for developing novel regimens to improve CRC treatment outcomes. In this study, we found that Tan IIA inhibits aerobic glycolysis in CRC cells via suppressing Skp2/Akt/HK2 signaling axis and thereby overcomes 5-Fu resistance. Specifically, Tan IIA induces ubiquitination-mediated Skp2 degradation by attenuating the interaction between USP2 and Skp2. Moreover, the combination of Tan IIA with USP2 inhibitor ML364 overcomes 5-Fu resistance in vitro and xenograft mouse models. This study elucidates a novel mechanism of 5-Fu resistance and offers a promising combination treatment option for overcoming chemoresistance.