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Int J Biol Sci 2023; 19(16):5204-5217. doi:10.7150/ijbs.83682 This issue Cite

Research Paper

Polyphyllin VII induces CTC anoikis to inhibit lung cancer metastasis through EGFR pathway regulation

Zujun Que^1,2†, Bin Luo^3†, Pan Yu^3†, Dan Qi^4,5†, Wenji Shangguan^2,6, Panpan Wang³, Jiajun Liu¹, Yan Li³, He Li⁶, Ronghu Ke⁴, Erxi Wu^4,5,7,8,9✉, Jianhui Tian^1,2,3✉

1. Institute of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine (TCM), Shanghai, 200071, China.
2. Institute of TCM Oncology, Longhua Hospital, Shanghai University of TCM, Shanghai, 200032, China.
3. Clinical Oncology Center, Shanghai Municipal Hospital of TCM, Shanghai University of TCM, Shanghai, 200071, China.
4. Department of Neurosurgery and Neuroscience Institute, Baylor Scott & White Health, Temple, TX 76508, USA.
5. Department of Neurosurgery, Baylor College of Medicine, Temple, Texas 76508, USA.
6. Department of TCM, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
7. School of Medicine, Texas A&M University, College Station, TX 77843, USA.
8. Irma Lerma Rangel School of Pharmacy, Texas A&M University, College Station, TX 77843, USA.
9. LIVESTRONG Cancer Institutes and Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA.
† Contributed equally to this work.

✉ Corresponding authors: tjhhawkedu.cn (J. Tian); erxi.wuorg (E. Wu).

Abstract

Circulating tumor cells (CTCs) are cells that detach from the primary tumor and enter the bloodstream, playing a crucial role in the metastasis of lung cancer. Unfortunately, there is currently a lack of drugs specifically designed to target CTCs and prevent tumor metastasis. In this study, we present evidence that polyphyllin VII, a potent anticancer compound, effectively inhibits the metastasis of lung cancer by inducing a process called anoikis in CTCs. We observed that polyphyllin VII had significant cytotoxicity and inhibited colony formation, migration, and invasion in both our newly established cell line CTC-TJH-01 and a commercial lung cancer cell line H1975. Furthermore, we found that polyphyllin VII induced anoikis and downregulated the TrkB and EGFR-MEK/ERK signaling pathways. Moreover, activation of TrkB protein did not reverse the inhibitory effect of polyphyllin VII on CTCs, while upregulation of EGFR protein effectively reversed it. Furthermore, our immunodeficient mouse models recapitulated that polyphyllin VII inhibited lung metastasis, which was associated with downregulation of the EGFR protein, and reduced the number of CTCs disseminated into the lungs by inducing anoikis. Together, these results suggest that polyphyllin VII may be a promising compound for the treatment of lung cancer metastasis by targeting CTCs.

Keywords: Lung cancer, Metastasis, Circulating tumor cells, Anoikis, Polyphyllin VII

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