2. Academic Validation
  3. Erianin reverses 5-FU resistance by targeting CALM1/CAMKK2 and activating autophagy in colorectal cancer

Erianin reverses 5-FU resistance by targeting CALM1/CAMKK2 and activating autophagy in colorectal cancer

  • Chem Biol Interact. 2025 Sep 19:421:111750. doi: 10.1016/j.cbi.2025.111750.
Fangyuan Zhou 1,  Luorui Shang 2,  Jinxiao Li 3,  Mengqi Zhang 4,  Shuhan Wang 5,  Yuju Cai 6,  Qifeng Lin 7,  Haiyang Gao 8,  Shenglan Yang 9
Affiliations

Affiliations

  • 1 Department of Clinical Nutrition, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: 2804255823@qq.com.
  • 2 Department of Clinical Nutrition, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: 602073578@qq.com.
  • 3 Department of Clinical Nutrition, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: 962939252@qq.com.
  • 4 Department of Clinical Nutrition, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: 3463911704@qq.com.
  • 5 Department of Clinical Nutrition, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: wangsh79@outlook.com.
  • 6 Department of Clinical Nutrition, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: 15827291897@163.com.
  • 7 Department of Clinical Nutrition, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: 1145230429@qq.com.
  • 8 Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: cnkaiyokou@gmail.com.
  • 9 Department of Clinical Nutrition, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: yangshenglan005@163.com.
PMID: 40976489 DOI: 10.1016/j.cbi.2025.111750
Abstract

Background: Chemoresistance represents a significant factor contributing to the failure of clinical treatments in colorectal Cancer (CRC), with resistance to 5-fluorouracil (5-FU) being notably prevalent. Erianin has demonstrated potential in reversing tumor resistance; however, its specific effects and underlying mechanisms in the context of 5-FU-resistant CRC require comprehensive validation.

Methods: The half-maximal inhibitory concentration (IC50) of Erianin and 5-FU was determined using the CCK8 assay. CRC cells resistant to 5-FU were induced by progressively increasing concentrations of 5-FU. Cellular proliferation, migration, and invasion were evaluated via 5-ethynyl-2'-deoxyuridine (EdU) assays, wound-healing assays, and Transwell Matrigel invasion assays. The expression levels of protein and mRNA expression levels for various molecules were quantified using Western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR). Immunofluorescence assays were employed to assess the expression of autophagy-related markers. The in vivo therapeutic efficacy of Erianin was assessed using a xenograft tumor model.

Results: Erianin effectively reinstated the sensitivity of 5-FU-resistant CRC cells to 5-FU, significantly reducing tumor cell proliferation, migration, and invasion, as well as inhibiting xenograft tumor growth. Mechanistic investigations demonstrated that Erianin targets and binds to the Calmodulin 1 (CALM1) protein, enhancing its stability and subsequently increasing the phosphorylation levels of CAMKK2. This interaction facilitates Autophagy in 5-FU-resistant CRC cells, ultimately leading to tumor cell death.

Conclusion: Erianin sensitized the resistant CRC cells to 5-FU by activating the CALM1/CAMKK2 signaling pathway, thereby inducing Autophagy. The combination of 5-FU and Erianin presents a promising therapeutic approach to enhance survival outcomes in patients with refractory CRC.

Keywords

5-Fluorouracil; Autophagy; Chemotherapy resistance; Colorectal cancer; Erianin.

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