2. Academic Validation
  3. YO2 Induces Melanoma Cell Apoptosis through p53-Mediated LRP1 Downregulation

YO2 Induces Melanoma Cell Apoptosis through p53-Mediated LRP1 Downregulation

  • Cancers (Basel). 2022 Dec 31;15(1):288. doi: 10.3390/cancers15010288.
Yousef Salama 1,  Satoshi Takahashi 2,  Yuko Tsuda 3,  Yoshio Okada 3,  Koichi Hattori 4,  Beate Heissig 5
Affiliations

Affiliations

  • 1 An-Najah Center for Cancer and Stem Cell Research, Faculty of Medicine and Health Sciences, An-Najah National University, P.O. Box 7, Nablus 99900800, Palestine.
  • 2 Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
  • 3 The Faculty of Pharmaceutical Science, Kobe Gakuin University, 518 Arise, Ikawadani-Cho, Nishi-Ku, Kobe 651-2180, Japan.
  • 4 Center for Genome and Regenerative Medicine, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-Ku, Tokyo 113-8421, Japan.
  • 5 Department of Research Support Utilizing Bioresource Bank, Graduate School of Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo 113-8421, Japan.
PMID: 36612285 DOI: 10.3390/cancers15010288
Abstract

The multifunctional endocytic receptor low-density lipoprotein receptor-related protein 1 (LRP1) has been implicated in melanoma growth. However, the mechanism of LRP1 expression in melanoma cells remains only partially understood. In most melanomas, the TP53 tumor suppressor is retained as a non-mutated, inactive form that fails to suppress tumors. We identify TP53 as a regulator of LRP1-mediated tumor growth. TP53 enhances the expression of miRNA miR-103/107. These miRNAs target LRP1 expression on melanoma cells. TP53 overexpression in human and murine melanoma cells was achieved using lentivirus or treatment with the small molecule YO-2, a plasmin inhibitor known to induce Apoptosis in various Cancer cell lines. TP53 restoration enhanced the expression of the tumor suppressor miR-103/107, resulting in the downregulation of LRP1 and suppression of tumor growth in vivo and in vitro. Furthermore, LRP1 overexpression or p53 downregulation prevented YO-2-mediated melanoma growth inhibition. We identified YO-2 as a novel p53 inducer in melanoma cells. Cotreatment of YO-2 with doxorubicin blocked tumor growth in vivo and in a murine melanoma model, suggesting that YO-2 exerts anti-melanoma effects alone or in combination with conventional myelosuppressive drugs.

Keywords

CD91; LRP1; PANK1; PLAT; melanoma; miR-103; miRNA; mir-107; p53.

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