Theranostics 2021; 11(3):1326-1344. doi:10.7150/thno.50564 This issue Cite

Research Paper

Identification of novel CD44v6-binding peptides that block CD44v6 and deliver a pro-apoptotic peptide to tumors to inhibit tumor growth and metastasis in mice

Fatima Khan1,2,3, Smriti Gurung1,2, Gowri Rangaswamy Gunassekaran1,2, Sri Murugan Poongkavithai Vadevoo1,2, Lianhua Chi1, Uttapol Permpoon1,2, Md. Enamul Haque1, Yun-Ki Lee1,2, Soo-Woong Lee1, Soyoun Kim1, Byungheon Lee1,2,3✉

1. Department of Biochemistry and Cell Biology, School Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Republic of Korea.
2. BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, School Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Republic of Korea.
3. CMRI, School Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Republic of Korea.

Citation:
Khan F, Gurung S, Gunassekaran GR, Vadevoo SMP, Chi L, Permpoon U, Haque ME, Lee YK, Lee SW, Kim S, Lee B. Identification of novel CD44v6-binding peptides that block CD44v6 and deliver a pro-apoptotic peptide to tumors to inhibit tumor growth and metastasis in mice. Theranostics 2021; 11(3):1326-1344. doi:10.7150/thno.50564. https://www.thno.org/v11p1326.htm
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Abstract

Graphic abstract

CD44v6, a splice variant of the cell surface glycoprotein CD44, acts as a co-receptor for c-Met and is upregulated in tumors with high metastatic potential.

Methods: We screened a phage-displayed peptide library for peptides that selectively bind to CD44v6-overexpressing cells and exploited them to block CD44v6 and deliver a pro-apoptotic peptide to tumors for cancer therapy.

Results: CNLNTIDTC (NLN) and CNEWQLKSC (NEW) peptides bound preferentially to CD44v6-high cells than to CD44v6-low cells. The binding affinities of NLN and NEW to CD44v6 protein were 253 ± 79 and 85 ± 18 nM, respectively. Peptide binding to CD44v6-high cells was inhibited by the knockdown of CD44v6 gene expression and competition with an anti-CD44v6 antibody. A pull-down assay with biotin-labeled peptides enriched CD44v6 from cell lysates. NLN and NEW induced CD44v6 internalization and inhibited hepatocyte growth factor-induced c-Met internalization, c-Met and Erk phosphorylation, and cell migration and invasion. In mice harboring tumors, intravenously administered NLN and NEW homed to the tumors and inhibited metastasis to the lungs. When combined with crizotinib, a c-Met inhibitor, treatment with each peptide inhibited metastatic growth more efficiently than each peptide or crizotinib alone. In addition, KLAKLAKKLAKLAK pro-apoptotic peptide guided by NLN (NLN-KLA) or NEW (NEW-KLA) killed tumor cells and inhibited tumor growth and metastasis. No significant systemic side effects were observed after treatments.

Conclusions: These results suggest that NLN and NEW are promising metastasis-inhibiting peptide therapeutics and targeting moieties for CD44v6-expressing metastases.

Keywords: CD44v6, c-Met, metastasis, peptide, phage display


Citation styles

APA
Khan, F., Gurung, S., Gunassekaran, G.R., Vadevoo, S.M.P., Chi, L., Permpoon, U., Haque, M.E., Lee, Y.K., Lee, S.W., Kim, S., Lee, B. (2021). Identification of novel CD44v6-binding peptides that block CD44v6 and deliver a pro-apoptotic peptide to tumors to inhibit tumor growth and metastasis in mice. Theranostics, 11(3), 1326-1344. https://doi.org/10.7150/thno.50564.

ACS
Khan, F.; Gurung, S.; Gunassekaran, G.R.; Vadevoo, S.M.P.; Chi, L.; Permpoon, U.; Haque, M.E.; Lee, Y.K.; Lee, S.W.; Kim, S.; Lee, B. Identification of novel CD44v6-binding peptides that block CD44v6 and deliver a pro-apoptotic peptide to tumors to inhibit tumor growth and metastasis in mice. Theranostics 2021, 11 (3), 1326-1344. DOI: 10.7150/thno.50564.

NLM
Khan F, Gurung S, Gunassekaran GR, Vadevoo SMP, Chi L, Permpoon U, Haque ME, Lee YK, Lee SW, Kim S, Lee B. Identification of novel CD44v6-binding peptides that block CD44v6 and deliver a pro-apoptotic peptide to tumors to inhibit tumor growth and metastasis in mice. Theranostics 2021; 11(3):1326-1344. doi:10.7150/thno.50564. https://www.thno.org/v11p1326.htm

CSE
Khan F, Gurung S, Gunassekaran GR, Vadevoo SMP, Chi L, Permpoon U, Haque ME, Lee YK, Lee SW, Kim S, Lee B. 2021. Identification of novel CD44v6-binding peptides that block CD44v6 and deliver a pro-apoptotic peptide to tumors to inhibit tumor growth and metastasis in mice. Theranostics. 11(3):1326-1344.

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