Abstract
Targeted tumor and efficient, specific biological drug delivery in vivo has been one of the main challenges in protein-based cancer-targeted therapies. Mitochondria are potential therapeutic targets for various anti-cancer drugs. We have previously reported that protein kinase Cα-mediated phosphorylation of Toxoplasma gondii GRA8 is required for mitochondrial trafficking and regulating the interaction of the C-terminal of GRA8 with ATP5A1/SIRT3 in mitochondria. Furthermore, SIRT3 facilitates ATP5A1 deacetylation, mitochondrial activation, and subsequent antiseptic activity in vivo. Herein we developed a recombinant acidity-triggered rational membrane (ATRAM)-conjugated multifunctional GRA8 peptide (rATRAM-G8-M/AS) comprising ATRAM as the cancer-targeting cell-penetrating peptide, and essential/minimal residues for mitochondrial targeting or ATP5A1/SIRT3 binding. This peptide construct showed considerably improved potency about cancer cell death via mitochondria activity and biogenesis compared with rGRA8 alone in HCT116 human carcinoma cells, reaching an IC50 value of up to 200-fold lower in vitro and 500-fold lower in vivo. Notably, rATRAM-G8-M/AS treatment showed significant therapeutic effects in a mouse xenograft model through mitochondrial metabolic resuscitation, and it produced negligible immunogenicity and immune responses in vivo. Thus, these results demonstrate that rATRAM-G8-M/AS represents a useful therapeutic strategy against tumors, particularly colon cancer. This strategy represents an urgently needed paradigm shift for therapeutic intervention.
Highlights
Cancer is the primary cause of mortality worldwide, and in the United States cancer related deaths are second only to heart disease related mortality [1]
We previously discovered that protein kinase Cα (PKCα)-phosphorylated T. gondii GRA8 is transferred to the mitochondria and interacts with mitochondrial SIRT3
Deacetylated ATP5A1 participates in several mitochondrial functions, and SIRT3 can orchestrate the overall changes in mitochondrial function, that are critical for cancer growth [14, 22]
Summary
Cancer is the primary cause of mortality worldwide, and in the United States cancer related deaths are second only to heart disease related mortality [1]. ATP production in mitochondria is regulated acetylation and deacetylation of many mitochondrial enzymes and NAD-dependent protein deacetylase sirtuin-3 (SIRT3) present in mitochondria plays an important role in this process [4,5,6]. Deciphering how the metabolic regulators in cancer cells are changed would help in the development of more effective anti-cancer therapies. Therapeutic approaches that target mitochondria are considered to provide novel means to combat cancer and to reduce associated mortality and even to reverse the oncogenic process. Such metabolic intervening measures, called “metabolic resuscitation”, employ either nutritional or pharmacological agents to improve mitochondrial function [2, 4, 7, 8]. The underlying mechanisms for the metabolic resuscitation induced by the dense granule protein GRA8 of Toxoplasma gondii (T. gondii) in tumor cells are yet to be investigated [8]
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