2. Academic Validation
  3. Inhibition of EREG/ErbB/ERK by Astragaloside IV reversed taxol-resistance of non-small cell lung cancer through attenuation of stemness via TGFβ and Hedgehog signal pathway

Inhibition of EREG/ErbB/ERK by Astragaloside IV reversed taxol-resistance of non-small cell lung cancer through attenuation of stemness via TGFβ and Hedgehog signal pathway

  • Cell Oncol (Dordr). 2024 Oct 7. doi: 10.1007/s13402-024-00999-7.
Wenhao Xiu # 1,  Yujia Zhang # 1 2,  Dongfang Tang # 3,  Sau Har Lee 4,  Rui Zeng 1,  Tingjie Ye 1,  Hua Li 1,  Yanlin Lu 5,  Changtai Qin 1,  Yuxi Yang 1,  Xiaofeng Yan 1,  Xiaoling Wang 1,  Xudong Hu 1,  Maoquan Chu 6,  Zhumei Sun 7,  Wei Xu 8
Affiliations

Affiliations

  • 1 School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 2 Department of Clinical Medicine, Suzhou Vocational Health College, Suzhou, Jiangsu, China.
  • 3 Department of Thoracic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, China.
  • 4 School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Selangor, Malaysia.
  • 5 Department of Oncology and Institute of Traditional Chinese Medicine in Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 6 School of Life Science and Technology, Tongji University, Shanghai, China.
  • 7 School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. sunzhumei2000@126.com.
  • 8 School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. wei-xu11@tsinghua.org.cn.
  • # Contributed equally.
PMID: 39373858 DOI: 10.1007/s13402-024-00999-7
Abstract

Purpose: Taxol is the first-line chemo-drug for advanced non-small cell lung Cancer (NSCLC), but it frequently causes acquired resistance, which leads to the failure of treatment. Therefore, it is critical to screen and characterize the mechanism of the taxol-resistance reversal agent that could re-sensitize the resistant Cancer cells to chemo-drug.

Method: The cell viability, sphere-forming and xenografts assay were used to evaluate the ability of ASIV to reverse taxol-resistance. Immunohistochemistry, cytokine application, small-interfering RNA, small molecule inhibitors, and RNA-seq approaches were applied to characterize the molecular mechanism of inhibition of Epiregulin (EREG) and downstream signaling by ASIV to reverse taxol-resistance.

Results: ASIV reversed taxol resistance through suppression of the stemness-associated genes of spheres in NSCLC. The mechanism exploration revealed that ASIV promoted the K48-linked polyubiquitination of EREG along with degradation. Moreover, EREG could be triggered by chemo-drug treatment. Consequently, EREG bound to the ErbB receptor and activated the ERK signal to regulate the expression of the stemness-associated genes. Inhibition of EREG/ErbB/ERK could reverse the taxol-resistance by inhibiting the stemness-associated genes. Finally, it was observed that TGFβ and Hedgehog signaling were downstream of EREG/ErbB/ERK, which could be targeted using inhibitors to reverse the taxol resistance of NSCLC.

Conclusions: These findings revealed that inhibition of EREG by ASIV reversed taxol-resistance through suppression of the stemness of NSCLC via EREG/ErbB/ERK-TGFβ, Hedgehog axis.

Keywords

ASIV; EREG; Non-small cell lung cancer; Stemness; Taxol-resistance.

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