Targeting Skp2 by Tanshinone IIA overcomes chemoresistance in colorectal cancer

Sep 23, 2026

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Fluorouracil (5-Fu)-based chemotherapy serves as a first-line option for advanced colorectal cancer, but long-term 5-Fu exposure frequently triggers chemoresistance and reduces therapeutic benefit. This study shows that Tanshinone IIA suppresses aerobic glycolysis in colorectal cancer cells by inhibiting the Skp2/Akt/HK2 signaling axis, thereby restoring sensitivity to 5-Fu. Mechanistically, Tanshinone IIA promotes ubiquitination-mediated Skp2 degradation by weakening USP2–Skp2 interaction. Combined treatment with a USP2 inhibitor (ML364) overcomes 5-Fu resistance in vitro and in xenograft mouse models.

LanguageEnglish

CategoryHealthcare

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Pages18

Reading Time45 min

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Cell Biol Toxicol (2025) 41:135 [https://doi.org/10.1007/s10565-025-10084-w](https://doi.org/10.1007/s10565-025-10084-w) Targeting Skp2 by Tanshinone IIA overcomeschemoresistance in colorectal cancer Xin Dong · Kexin Li · Ruirui Wang · Baojun Wei · Yiling Li · Yu Zhang · Shengkai Huang · Guojing Wang · Quanquan Gao · Wei Li · Wei Cui Received: 29 May 2025 / Accepted: 29 August 2025 © The Author(s) 2025 Abstract 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. | Xin Dong, Kexin Li, and Ruirui Wang contributed equally to this work. | | --- | | Supplementary Information The online version contains supplementary material available at [https://doi](https://doi). org/10.1007/s10565-025-10084-w. | X. Dong · K. Li · R. Wang · B. Wei · Y. Li · Y. Zhang · S. Huang · G. Wang · Q. Gao · W. Cui (*) Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China [e-mail: wendycuiwei@sina.cn](e-mail: wendycuiwei@sina.cn) [R. Wang](R. Wang) · W. Li (*) Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China [e-mail: weililx@csu.edu.cn](e-mail: weililx@csu.edu.cn) This study elucidates a novel mechanism of 5-Fu resistance and offers a promising combination treatment option for overcoming chemoresistance. Keywords Colorectal cancer · Glycolysis · Tanshinone IIA · Skp2 · HK2 Introduction Colorectal cancer (CRC), a prevalent digestive tract cancer, is the third most frequent cancer and exhibits a high mortality rate worldwide (Chen et al. 2022 ; Xi and Xu 2021) . Several etiologies have been demonstrated to be related to the pathogenesis of CRC, encompassing genetic predispositions and environmental influences, such as obesity, smoking and alcohol intake (Bien and Lin 2021; Li et al. 2022b, 2022c; Jiang et al. 2022b, 2022c; Hull et al. 2020) . The rapid development of multi-disciplines, early screening and diagnosis, and multiple treatment strategies, such as surgery, radiotherapy, immunotherapy, chemotherapy and combination therapeutic strategies have yielded some benefits for colorectal cancer patients (Wang and Pan 2022 ; Kavitha et al. 2022 ; Yang et al. 2022 ; Shinji et al. 2022) . However, adverse effects and therapeutic resistance remain the major obstacles to clinical treatment (Deng et al. 2022 ; Peña et al. 2022) . Exploring the potential mechanisms of treatment failure and discovering alternative treatment approaches are critically urgent. The metabolic reprogramming, switching from oxidative phosphorylation (OXPHOS) to glycolysis to support genome replication and rapid growth even in oxygen-sufficient environments, is a primary characteristic of energy metabolism in cancer cells, which is known as the aerobic glycolysis or “Warburg effect”(Fukushi et al. 2022; Jiang et al. 2022a) . The glycolysis pathway is controlled by certain metabolic enzymes, including phosphoglycerate kinase 1 (PGK1), phosphofructokinase (PFK), and hexokinase (HK), which are responsible for the abnormally activated energy metabolism of cancer cells (Lunt and Vander Heiden 2011; VanDer Heiden et al. 2009) . Among them, HK, as the first step enzyme in glycolysis (Seiler et al. 2022), c

FAQs

What problem does the study address in colorectal cancer treatment?

The study addresses 5-Fu resistance that develops during long-term chemotherapy, limiting its effectiveness in advanced colorectal cancer.

How does Tanshinone IIA act against 5-Fu resistance?

Tanshinone IIA inhibits aerobic glycolysis by suppressing the Skp2/Akt/HK2 signaling axis, leading to overcoming 5-Fu resistance.

What mechanism drives Skp2 reduction in this study?

Tanshinone IIA induces ubiquitination-mediated Skp2 degradation by attenuating the interaction between USP2 and Skp2.

Sep 23, 2026

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