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

Manikandan Santhanam; Swaroop Kumar Pandey; Anna Shteinfer-Kuzmine; Avijit Paul; Nur Abusiam; Ran Zalk; Varda Shoshan-Barmatz

doi:10.1016/j.ymthe.2024.04.007

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

Mol Ther. 2024 Apr 5:S1525-0016(24)00223-5. doi: 10.1016/j.ymthe.2024.04.007. Online ahead of print.

Authors

Manikandan Santhanam¹, Swaroop Kumar Pandey¹, Anna Shteinfer-Kuzmine², Avijit Paul³, Nur Abusiam², Ran Zalk⁴, Varda Shoshan-Barmatz⁵

Affiliations

¹ 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.
² The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 0084105, Israel.
³ Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva 0084105, Israel.
⁴ Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Beer Sheva 0084105, Israel.
⁵ 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.

PMID: 38582961
DOI: 10.1016/j.ymthe.2024.04.007

Abstract

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.

Keywords: SMAC/diablo; apoptosis; cancer stem cells; cell death; immunosuppression; inflammation; lung cancer; peptide array; peptides; survivin/BIRC5.