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تحميل

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.

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