2. Academic Validation
  3. Calcipotriol abrogates cancer-associated fibroblast-derived IL-8-mediated oxaliplatin resistance in gastric cancer cells via blocking PI3K/Akt signaling

Calcipotriol abrogates cancer-associated fibroblast-derived IL-8-mediated oxaliplatin resistance in gastric cancer cells via blocking PI3K/Akt signaling

  • Acta Pharmacol Sin. 2022 Jun 8. doi: 10.1038/s41401-022-00927-1.
Zhen-Xiong Zhao  # 1 2,  Yan-Qiu Zhang  # 2 3,  Hui Sun  # 2 4 5,  Zi-Qi Chen  # 6,  Jin-Jia Chang 2 3,  Xin Wang 2 4 5,  Xu Wang 2 4 5,  Cong Tan 2 4 5,  Shu-Juan Ni 2 4 5,  Wei-Wei Weng 2 4 5,  Meng Zhang 2 4 5,  Lei Wang 2 4 5,  Dan Huang 2 4 5,  Yun Feng 7,  Wei-Qi Sheng 8 9 10,  Mi-Die Xu 11 12 13
Affiliations

Affiliations

  • 1 Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
  • 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • 3 Department of Gastrointestinal Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
  • 4 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
  • 5 Institute of Pathology, Fudan University, Shanghai, 200032, China.
  • 6 Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200080, China.
  • 7 Department of Gastroenterology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200080, China. yun.feng2@shgh.cn.
  • 8 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. shengwq@shca.org.cn.
  • 9 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. shengwq@shca.org.cn.
  • 10 Institute of Pathology, Fudan University, Shanghai, 200032, China. shengwq@shca.org.cn.
  • 11 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. midiexu12@fudan.edu.cn.
  • 12 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. midiexu12@fudan.edu.cn.
  • 13 Institute of Pathology, Fudan University, Shanghai, 200032, China. midiexu12@fudan.edu.cn.
  • # Contributed equally.
PMID: 35676532 DOI: 10.1038/s41401-022-00927-1
Abstract

Activation of vitamin D receptor (VDR) in cancer-associated fibroblasts (CAFs) has been implicated in hesitating tumor progression and chemoresistance of several human malignancies. Yet, the role of VDR in CAF-induced chemotherapy resistance of gastric Cancer (GC) cells remains elusive. In this study we first conducted immunohistochemistry analysis on tissue microarrays including 88 pairs of GC and normal mucosa samples, and provided clinical evidence that VDR was mainly expressed in gastric mucous cells but almost invisible in CAFs, and VDR expression was negatively correlated with malignant clinical phenotype and advanced stages, low VDR expression confers to poor overall survival rate of patients with GC. In a co-culture system of primary CAFs and Cancer cells, we showed that treatment of HGC-27 and AGS GC cells with VDR ligand calcipotriol (Cal, 500 nM) significantly inhibited CAF-induced oxaliplatin resistance. By using RNA-sequencing and Human Cytokine Antibody Array, we demonstrated that IL-8 secretion from CAFs induced oxaliplatin resistance via activating the PI3K/Akt pathway in GC, whereas Cal treatment greatly attenuated the tumor-supportive effect of CAF-derived IL-8 on GC cells. Taken together, this study verifies the specific localization of VDR in GC tissues and demonstrates that activation of VDR abrogates CAF-derived IL-8-mediated oxaliplatin resistance in GC via blocking PI3K/Akt signaling, suggesting vitamin D supplementation as a potential strategy of enhancing the anti-tumor effect of chemotherapy in GC.

Keywords

IL-8; PI3K/AKT pathway; Vitamin D receptor; calcipotriol; cancer-associated fibroblasts; chemoresistance; gastric cancer; oxaliplatin; tumor microenvironment.

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