LXXLL peptide converts transportan 10 to a potent inducer of apoptosis in breast cancer cells.
Degenerate expression of transcription coregulator proteins is observed in most human cancers. Therefore, in targeted anti-cancer therapy development, intervention at the level of cancer-specific transcription is of high interest. The steroid receptor coactivator-1 (SRC-1) is highly expressed in breast, endometrial, and prostate cancer. It is present in various transcription complexes, including those containing nuclear hormone receptors. We examined the effects of a peptide that contains the LXXLL-motif of the human SRC-1 nuclear receptor box 1 linked to the cell-penetrating transportan 10 (TP10), hereafter referred to as TP10-SRC1LXXLL, on proliferation and estrogen-mediated transcription of breast cancer cells in vitro. Our data show that TP10-SRC1LXXLL induced dose-dependent cell death of breast cancer cells, and that this effect was not affected by estrogen receptor (ER) status. Surprisingly TP10-SRC1LXXLL severely reduced the viability and proliferation of hormone-unresponsive breast cancer MDA-MB-231 cells. In addition, the regulation of the endogenous ERα direct target gene pS2 was not affected by TP10-SRC1LXXLL in estrogen-stimulated MCF-7 cells. Dermal fibroblasts were similarly affected by treatment with higher concentrations of TP10-SRC1LXXLL and this effect was significantly delayed. These results suggest that the TP10-SRC1LXXLL peptide may be an effective drug candidate in the treatment of cancers with minimal therapeutic options, for example ER-negative tumors.
Protobios LLC, Mäealuse 4, Tallinn 12618, Estonia. kairit@protobios.com.
Kairit
K
Tints
Protobios LLC, Mäealuse 4, Tallinn 12618, Estonia. madis@protobios.com.
Madis
M
Prink
Protobios LLC, Mäealuse 4, Tallinn 12618, Estonia. tom@protobios.com.
Toomas
T
Neuman
Protobios LLC, Mäealuse 4, Tallinn 12618, Estonia. kaia@protobios.com.
Kaia
K
Palm
D020816:Amino Acid Motifs; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D061986:MCF-7 Cells; D009419:Nerve Tissue Proteins / Q000235:genetics*; D056920:Nuclear Receptor Coactivator 1 / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology*; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins / Q000187:drug effects
C405928:CDK5RAP3 protein, human; D018797:Cell Cycle Proteins; D057846:Cell-Penetrating Peptides; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; C586078:transportan-10; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1