A Screened GPR1 Peptide Exerts Antitumor Effects on Triple-Negative Breast Cancer

Abstract

The adipokine chemerin has been considered an important regulator of tumor immune surveillance. Chemerin recruits leukocytes through the receptor CMKLR1 to improve clinical outcomes of tumors and overall patient survival, but the role of GPR1 in tumors has not been widely investigated. Here, we found that GPR1 expression is elevated in breast cancerespecially triple-negative breast cancer (TNBC) tissues and cell lines. Herein, we screened a phage display peptide library to identify LRH7-G5, a peptide antagonist that blocks chemerin/GPR1 signaling. This peptide performed as an anticancer agent to suppress the proliferation of the TNBC cell lines MDA-MB-231 and HCC1937 but has little effect on T47D cells. LRH7-G5 treatment significantly blocked tumor growth in a TNBC cell-bearing orthotopic mouse model. Last, our results showed that this peptide's antitumor role is mediated through the PI3K/AKT signaling pathway. In conclusion, these data collectively suggest that the chemerin receptor GPR1 is a novel target for controlling TNBC progression and establish peptide LRH7-G5 as a new therapeutic agent for suppressing TNBC tumor growth.

Chemerin: A Functional Adipokine in Reproductive Health and Diseases

“…The biological role of GPR1 and CCRL2 remains largely unknown, and no small-molecule antagonists targeting these two receptors have been found until now. By utilizing the phage display techniques, our group screened a series of peptides binding with the CMKLR1 (unpublished study) or GPR1 [ 136 ]. The GPR1-binding peptide was evidenced to inhibit the triple-negative breast carcinoma [ 136 ] and improve LPS-Induced depressant-like behaviors and ovarian functions [ 42 ] in vivo.…”

“…In parallel, recombinant chemerin treatment suppressed tumor growth in an MCF-7 cell-derived xenograft model and reduced the progression of osteolytic lesions in an MDA-MB-231 cell-induced osteolysis model [ 135 ]. On the other side, GPR1 was discovered to elevate in triple-negative breast cancer (TNBC) specimens and cell lines, and GPR1 binding peptide screened by phage display technology exhibited antineoplastic effects against TNBC in vitro and in vivo [ 136 ].…”

Chemerin enhances mesenchymal features of glioblastoma by establishing autocrine and paracrine networks in a CMKLR1-dependent manner

“…Similar with our findings in GBM, the expression level of chemerin in tumor tissue or serum is negatively correlated with patient survival in cancers such as breast cancer [ 43 , 44 ], ovarian cancer [ 45 ], and non-small cell lung cancer [ 46 ]. In these cancers, chemerin could facilitate their progression mainly by promoting their invasive ability [ 47 – 49 ], although its influence on tumor proliferation is relatively negligible [ 13 , 50 ] or even suppressive [ 51 ]. This characteristic functional change is similar to what in cancers that have undergone epithelial-to-mesenchymal transformation (EMT).…”

The Screening of Therapeutic Peptides for Anti-Inflammation through Phage Display Technology

“…The GPR1-specific peptide LRH7-G5, which competes with chemerin to block chemerin/GPR1 signaling, was screened from the Ph.D.-7 random phage library. The anti-tumor response of this peptide was found to be dose-dependent, inhibiting the proliferation of TNBC cell lines MDA-MB-231 and HCC1937 and suppressing tumor growth, but not T47D cells, through phosphatidylinositol-3-kinase (PI3K)/V-akt murine thymoma viral oncogene homolog (AKT) signaling [ 30 ].…”