Class IV Lasso Peptides Synergistically Induce Proliferation of Cancer Cells and Sensitize Them to Doxorubicin

Jaime Felipe Guerrero-Garzón; Eva Madland; Martin Zehl; Madhurendra Singh; Shiva Rezaei; Finn L Aachmann; Gaston Courtade; Ernst Urban; Christian Rückert; Tobias Busche; Jörn Kalinowski; Yan-Ru Cao; Yi Jiang; Cheng-Lin Jiang; Galina Selivanova; Sergey B Zotchev

doi:10.1016/j.isci.2020.101785

Class IV Lasso Peptides Synergistically Induce Proliferation of Cancer Cells and Sensitize Them to Doxorubicin

iScience. 2020 Nov 10;23(12):101785. doi: 10.1016/j.isci.2020.101785. eCollection 2020 Dec 18.

Authors

Jaime Felipe Guerrero-Garzón¹, Eva Madland², Martin Zehl³, Madhurendra Singh⁴, Shiva Rezaei^{4

5}, Finn L Aachmann², Gaston Courtade², Ernst Urban⁶, Christian Rückert⁷, Tobias Busche⁷, Jörn Kalinowski⁷, Yan-Ru Cao⁸, Yi Jiang⁸, Cheng-Lin Jiang⁸, Galina Selivanova⁴, Sergey B Zotchev¹

Affiliations

¹ Department of Pharmacognosy, University of Vienna, Vienna 1090, Austria.
² NOBIPOL, Department of Biotechnology and Food Science, NTNU Norwegian University of Science and Technology, 7034 Trondheim, Norway.
³ Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna 1090, Austria.
⁴ Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17165 Stockholm, Sweden.
⁵ Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
⁶ Department of Pharmaceutical Chemistry, University of Vienna, Vienna 1090, Austria.
⁷ Center for Biotechnology, Bielefeld University, Universitätsstraße 27, 33615 Bielefeld, Germany.
⁸ Yunnan Institute of Microbiology, Yunnan University, 650091 Kunming, P.R.China.

Abstract

Heterologous expression of a biosynthesis gene cluster from Amycolatopsis sp. resulted in the discovery of two unique class IV lasso peptides, felipeptins A1 and A2. A mixture of felipeptins stimulated proliferation of cancer cells, while having no such effect on the normal cells. Detailed investigation revealed, that pre-treatment of cancer cells with a mixture of felipeptins resulted in downregulation of the tumor suppressor Rb, making the cancer cells to proliferate faster. Pre-treatment with felipeptins made cancer cells considerably more sensitive to the anticancer agent doxorubicin and re-sensitized doxorubicin-resistant cells to this drug. Structural characterization and binding experiments showed an interaction between felipeptins resulting in complex formation, which explains their synergistic effect. This discovery may open an alternative avenue in cancer treatment, helping to eliminate quiescent cells that often lead to cancer relapse.

Keywords: Biochemistry; Biological Sciences; Biotechnology; Microbiology.