Ganoderic acid D attenuates gemcitabine resistance of triple-negative breast cancer cells by inhibiting glycolysis via HIF-1α destabilization

Binbin Luo; Linyi Song; Limiao Chen; Yue Cai; Mingwei Zhang; Shenyi Wang

doi:10.1016/j.phymed.2024.155675

Ganoderic acid D attenuates gemcitabine resistance of triple-negative breast cancer cells by inhibiting glycolysis via HIF-1α destabilization

Phytomedicine. 2024 Apr 23:129:155675. doi: 10.1016/j.phymed.2024.155675. Online ahead of print.

Authors

Binbin Luo¹, Linyi Song², Limiao Chen³, Yue Cai³, Mingwei Zhang³, Shenyi Wang⁴

Affiliations

¹ School of Integrated Traditional Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China; Department of Science and Education, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, 230011, China. Electronic address: 444266748@qq.com.
² School of Integrated Traditional Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China; Department of Science and Education, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, 230011, China.
³ School of Integrated Traditional Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China.
⁴ School of Integrated Traditional Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China; Institute of Integrated Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei, Anhui, 230012, China. Electronic address: guikbvder@ahtcm.edu.cn.

PMID: 38678954
DOI: 10.1016/j.phymed.2024.155675

Abstract

Background: Gemcitabine (GEM) resistance is the primary reason why combination chemotherapy is limited in triple-negative breast cancer (TNBC). Ganoderic acid D (GAD), a natural triterpenoid compound obtained from Ganoderma lucidum, has been shown to have antitumor activities. However, whether GAD can reverse GEM resistance in TNBC requires further investigation.

Purpose: This study investigated whether and how GAD could reverse GEM resistance in TNBC as an antitumor adjuvant.

Methods: The effects of GAD on cell proliferation, cell cycle, and glycolysis were studied in vitro using a GEM-resistant (GEM-R) TNBC cell model. We enriched key pathways affected by GAD using proteomics techniques. Western blotting and qPCR were used to detect the expression of glycolysis-related genes after GAD treatment. A mouse resistance model was established using GEM-R TNBC cells, and hematoxylin-eosin staining and immunohistochemistry were used to assess the role of GAD in reversing resistance in vivo.

Results: Cellular functional assays showed that GAD significantly inhibited proliferation and glucose uptake in GEM-R TNBC cells. GAD reduces HIF-1α accumulation in TNBC cells under hypoxic conditions through the ubiquitinated protease degradation pathway. Mechanistically, GAD activates the p53/MDM2 pathway, promoting HIF-1α ubiquitination and proteasomal degradation and downregulating HIF-1α-dependent glycolysis genes like GLUT1, HK2, and PKM2. Notably, GAD combined with gemcitabine significantly reduced the growth of GEM-R TNBC cells in a subcutaneous tumor model.

Conclusions: This study reveals a novel antitumor function of GAD, which inhibits glycolysis by promoting HIF-1α degradation in GEM-R TNBC cells, offering a promising therapeutic strategy for TNBC patients with GEM resistance.

Keywords: Ganoderic acid D; Gemcitabine resistance; Glycolysis; HIF-1α; Triple-negative breast cancer.