Anti-ENO1 antibody combined with metformin against tumor resistance: a novel antibody-based platform

Xiong Shu; Hui Wen Zhang; Shi Ya Liu; Li Xin Sun; Tao Zhang; Yu Liang Ran

doi:10.7717/peerj.16817

Anti-ENO1 antibody combined with metformin against tumor resistance: a novel antibody-based platform

PeerJ. 2024 Mar 18:12:e16817. doi: 10.7717/peerj.16817. eCollection 2024.

Authors

Xiong Shu¹, Hui Wen Zhang², Shi Ya Liu², Li Xin Sun², Tao Zhang³, Yu Liang Ran²

Affiliations

¹ National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing JiShuiTan Hospital, Beijing, China.
² State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
³ The Second People's Hospital of Xining, Xining, China.

Abstract

Background: Antibody-based platforms (i.e., ADC) have emerged as one of the most encouraging tools for the cancer resistance caused by cancer stem cells (CSCs) enrichment. Our study might provide a promising therapeutic direction against drug resistance and serve as a potential precursor platform for screening ADC.

Methods: The cell migration, invasion, drug resistance, and self-renewal were assessed by the cell invasion and migration assay, wound healing assay, CCK-8 assay, colony formation assay, and sphere formation assay, respectively. The expression profiles of CSCs (ALDH⁺ and CD44⁺) subpopulations were screened by flow cytometry. The western blot and cell immunofluorescence assay were used to evaluate pathway-related protein expression in both anti-ENO1 antibody, MET combined with DPP/CTX-treated CSCs.

Results: In the present study, western blot and flow cytometry verified that anti-ENO1 antibody target the CD44⁺ subpopulation by inhibiting the PI3K/AKT pathway, while metformin might target the ALDH⁺ subpopulation through activation of the AMPK pathway and thus reverse drug resistance to varying degrees. Subsequently, in vitro investigation indicated that anti-ENO1 antibody, metformin combined with cisplatin/cetuximab could simultaneously target ALDH⁺ and CD44⁺ subpopulations. The combination also inhibited the CSCs proliferation, migration, invasion, and sphere formation; which may result in overcoming the drug resistance. Then, molecular mechanism exploration verified that the anti-ENO1 antibody, metformin combined with cisplatin/cetuximab inhibited the Wnt/β-catenin signaling.

Conclusions: The study preliminarily revealed anti-ENO1 antibody combined with metformin could overcome drug resistance against CSCs by inhibiting the Wnt//β-catenin pathway and might serve as a potential precursor platform for screening ADC. More importantly, it is reasonably believed that antibody-based drug combination therapy might function as an encouraging tool for oncotherapy.

Keywords: Antibody-based drug combination therapy; Cancer stem cells; Drug resistance; ENO1; Oncotherapy.

MeSH terms

Cell Line, Tumor
Cetuximab
Cisplatin / pharmacology
Metformin* / pharmacology
Phosphatidylinositol 3-Kinases / metabolism
beta Catenin / metabolism

Substances

Metformin
Cisplatin
beta Catenin
Cetuximab
Phosphatidylinositol 3-Kinases

Grants and funding

The study was supported by the CAMS Innovation Fund for Medical Sciences [grant number, 2021-I2M-1-067]; the National Natural Science Foundation of China [grant number, 82073278]; the Beijing Natural Science Foundation [grant number, 7222012]; Beijing Municipal Health Commission [grant number, BMHC-2019-9, and BMHC-2021-6]; the Independent Issue of State Key Laboratory of Molecular Oncology [grant number, SKLMO-2021-17]; and the Qinghai Provincial Science and Technology Department Applied Basic Research Program [grant number, 2020-ZJ-779]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.