Abstract
Malignant melanoma is the main cause of death in patients with skin cancer. Overexpression of Proteolipid protein 2 (PLP2) increased tumor metastasis and the knockdown of PLP2 inhibited the growth and metastasis of melanoma cells. In the present work, we studied the antitumor activity of peptide Rb4 derived from protein PLP2. In vitro, Rb4 induced F-actin polymerization, prevented F-actin depolymerization and increased the ER-derived cytosolic calcium. Such effects were associated with necrosis of murine melanoma B16F10-Nex2 cells and with inhibition of the viability of human cancer cell lines. Loss of plasma membrane integrity, dilation of mitochondria, cytoplasm vacuolation and absence of chromatin condensation characterized tumor cell necrosis. Cleavage of PARP-1 and inhibition of RIP1 expression were also observed. In vivo, peptide Rb4 reduced the lung metastasis of tumor cells and delayed the subcutaneous melanoma growth in a syngeneic model. Rb4 induced the expression of two DAMPs molecules, HMGB1 and calreticulin, in B16F10-Nex2. Our results suggest that peptide Rb4 acts directly on tumor cells inducing the expression of DAMPs, which trigger the immunoprotective effect in vivo against melanoma cells. We suggest that peptide Rb4 is a promising compound to be developed as an anticancer drug.
Highlights
Peptides play an important role in cell biology and in many diseases including cancer
No activity was observed for the scrambled Rb4 peptide (Scr-Rb4) in all the performed tests
The murine non-tumorigenic cell line Mouse embryonic fibroblasts (MEF) was unaffected by the highest concentration of Rb4 (1 mM)
Summary
Peptides play an important role in cell biology and in many diseases including cancer. Other peptides may induce specific T cell responses targeting tumor cells[6]. Various therapeutic peptides have been selectively designed to inhibit signal transduction pathways[7] and the cell cycle[8], induce cell death[9], target tumor suppressor p roteins[10] as well as block transcription factors[11]. Breitwieser et al.[15] reported that PLP2 multimerizes and functions as an ion channel due to the similarity of its hydropath profile with that of a subunit of the H+ vacuolar ATPase. PLP2, a four-transmembrane domain protein, has contributed to the tumor formation and metastasis of murine melanoma in a syngeneic B16F10 m odel[17,18]. We report on the therapeutic effect of Rb4 in a wellestablished metastatic and subcutaneous murine melanoma model
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