Interaction of SMAC with a survivin-derived peptide alters essential cancer hallmarks: Tumor growth, inflammation, and immunosuppression.

Autor:	Santhanam M; Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva 0084105, Israel; The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 0084105, Israel., Kumar Pandey S; Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva 0084105, Israel; The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 0084105, Israel., Shteinfer-Kuzmine A; The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 0084105, Israel., Paul A; Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva 0084105, Israel., Abusiam N; The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 0084105, Israel., Zalk R; Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Beer Sheva 0084105, Israel., Shoshan-Barmatz V; Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva 0084105, Israel; The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 0084105, Israel. Electronic address: vardasb@bgu.ac.il.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2024 Jun 05; Vol. 32 (6), pp. 1934-1955. Date of Electronic Publication: 2024 Apr 05.
DOI:	10.1016/j.ymthe.2024.04.007
Abstrakt:	Second mitochondrial-derived activator of caspase (SMAC), also known as direct inhibitor of apoptosis-binding proteins with low pI (Diablo), is known as a pro-apoptotic mitochondrial protein released into the cytosol in response to apoptotic signals. We recently reported SMAC overexpression in cancers as essential for cell proliferation and tumor growth due to non-apoptotic functions, including phospholipid synthesis regulation. These functions may be associated with its interactions with partner proteins. Using a peptide array with 768 peptides derived from 11 selected SMAC-interacting proteins, we identified SMAC-interacting sequences. These SMAC-binding sequences were produced as cell-penetrating peptides targeted to the cytosol, mitochondria, or nucleus, inhibiting cell proliferation and inducing apoptosis in several cell lines. For in vivo study, a survivin/baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5)-derived peptide was selected, due to its overexpression in many cancers and its involvement in mitosis, apoptosis, autophagy, cell proliferation, inflammation, and immune responses, as a target for cancer therapy. Specifically, a SMAC-targeting survivin/BIRC5-derived peptide, given intratumorally or intravenously, strongly inhibited lung tumor growth, cell proliferation, angiogenesis, and inflammation, induced apoptosis, and remodeled the tumor microenvironment. The peptide promoted tumor infiltration of CD-8 + cells and increased cell-intrinsic programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) expression, resulting in cancer cell self-destruction and increased tumor cell death, preserving immune cells. Thus, targeting the interaction between the multifunctional proteins SMAC and survivin represents an innovative therapeutic cancer paradigm. Competing Interests: Declaration of interests The authors declare that there are no competing interests. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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