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
Affiliations
Jaime Felipe Guerrero-Garzón
Department of Pharmacognosy, University of Vienna, Vienna 1090, Austria
Eva Madland
NOBIPOL, Department of Biotechnology and Food Science, NTNU Norwegian University of Science and Technology, 7034 Trondheim, Norway
Martin Zehl
Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna 1090, Austria
Madhurendra Singh
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17165 Stockholm, Sweden
Shiva Rezaei
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17165 Stockholm, Sweden; Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
Finn L. Aachmann
NOBIPOL, Department of Biotechnology and Food Science, NTNU Norwegian University of Science and Technology, 7034 Trondheim, Norway
Gaston Courtade
NOBIPOL, Department of Biotechnology and Food Science, NTNU Norwegian University of Science and Technology, 7034 Trondheim, Norway
Ernst Urban
Department of Pharmaceutical Chemistry, University of Vienna, Vienna 1090, Austria
Christian Rückert
Center for Biotechnology, Bielefeld University, Universitätsstraße 27, 33615 Bielefeld, Germany
Tobias Busche
Center for Biotechnology, Bielefeld University, Universitätsstraße 27, 33615 Bielefeld, Germany
Jörn Kalinowski
Center for Biotechnology, Bielefeld University, Universitätsstraße 27, 33615 Bielefeld, Germany
Yan-Ru Cao
Yunnan Institute of Microbiology, Yunnan University, 650091 Kunming, P.R.China
Yi Jiang
Yunnan Institute of Microbiology, Yunnan University, 650091 Kunming, P.R.China
Cheng-lin Jiang
Yunnan Institute of Microbiology, Yunnan University, 650091 Kunming, P.R.China
Galina Selivanova
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17165 Stockholm, Sweden; Corresponding author
Sergey B. Zotchev
Department of Pharmacognosy, University of Vienna, Vienna 1090, Austria; Corresponding author
Summary: 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.
