Abstract
BackgroundChemoresistance is one of the main problems in treatment of cancer. Periostin (PN) is a stromal protein which is mostly secreted from cancer associated fibroblasts in the tumor microenvironment and can promote cancer progression including cell survival, metastasis, and chemoresistance. The main objective of this study was to develop an anti-PN peptide from the bacteriophage library to overcome PN effects in breast cancer (BCA) cells.MethodsA twelve amino acids bacteriophage display library was used for biopanning against the PN active site. A selected clone was sequenced and analyzed for peptide primary structure. A peptide was synthesized and tested for the binding affinity to PN. PN effects including a proliferation, migration and a drug sensitivity test were performed using PN overexpression BCA cells or PN treatment and inhibited by an anti-PN peptide. An intracellular signaling mechanism of inhibition was studied by western blot analysis. Lastly, PN expressions in BCA patients were analyzed along with clinical data.ResultsThe results showed that a candidate anti-PN peptide was synthesized and showed affinity binding to PN. PN could increase proliferation and migration of BCA cells and these effects could be inhibited by an anti-PN peptide. There was significant resistance to doxorubicin in PN-overexpressed BCA cells and this effect could be reversed by an anti-PN peptide in associations with phosphorylation of AKT and expression of survivin. In BCA patients, serum PN showed a correlation with tissue PN expression but there was no significant correlation with clinical data.ConclusionsThis finding supports that anti-PN peptide is expected to be used in the development of peptide therapy to reduce PN-induced chemoresistance in BCA.
Highlights
Chemoresistance is one of the main problems in treatment of cancer
PN expression is up-regulated in the tumor microenvironment (TME) of many types of cancer, for example, non-small cell lung cancer (NSCLC) [5], malignant pleural mesothelioma [6], prostate cancer [7], renal cell carcinoma [8], cholangiocarcinoma (CCA) [9] and breast cancer (BCA) [10]
Expression of integrins in BCA cell lines and PN transfection BCA cells were used to check the expressions of integrin α5, α6, αV, β1, β 3, β 4 and β5 by real time reverse transcriptase (RT)-polymerase chain reaction (PCR) and all cells showed detection of signal amplification (Fig. S1)
Summary
Periostin (PN) is a stromal protein which is mostly secreted from cancer associated fibroblasts in the tumor microenvironment and can promote cancer progression including cell survival, metastasis, and chemoresistance. The mortality of cancer is attributed to various processes in cancer progression, including metastasis, proliferation and chemoresistance. These processes were influenced by the properties of cancer cells themselves and to the effects of the tumor microenvironment (TME). Periostin (PN) is one of active molecules in TME that has been reported to be a promoter of cancer progression through various mechanisms including proliferation, invasion/migration, angiogenesis and chemoresistance [3, 4]. Chemoresistance is one of the main difficulties for cancer treatment that can lead to mortality of the patients, the understanding and manipulation of chemoresistance can support patient survival
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