Abstract
Protein kinases, the main regulators of a vast map of cellular processes, are the most attractive targets in drug discovery. Despite a few successful examples of protein kinase inhibitors, the drug discovery strategy of downregulating protein kinase activity has been quite limited and often fails even in animal models. Here, we utilize protein kinase A (PKA) activity to design PKA-triggered supramolecular assemblies with anticancer activities. Grafting a suitable peptide to PNIPAM raises the critical temperature of the LCST polymer above body temperature. Interestingly, the corresponding phosphorylated polymer has a critical temperature below body temperature, making this peptide-appended PNIPAM a suitable polymer for the PKA-triggered supramolecular assembly process. PKA-triggered assembly occurs selectively in PKA-upregulated MCF-7 cells, which disturbs the cytoskeleton and sensitizes cancer cells against doxorubicin. The chemosensitization is also observed in vivo to identify effective tumor inhibitors with satisfactory biocompatibility. Overall, this phosphorylation-induced (in principle, PKA-catalyzed) supramolecular assembly opens up a promising chemotherapy strategy for combating kinase-upregulated cancer.
Highlights
Protein kinases, which constitute almost 2% of human genes, regulate a vast map of cellular processes by mediating the phosphorylation of their substrates.[1]
gel permeation chromatography (GPC) revealed its Scheme 1 Protein kinase A-triggered intracellular assemblies that can enhance the potency of doxorubicin by weakening the cell membrane
We demonstrated an example of phosphorylation-induced supramolecular assembly and hydrogelation via the combination of self-assembling peptides and the lower critical solution temperature (LCST) polymer poly(N-isopropyl acrylamide) (PNIPAM)
Summary
Protein kinases, which constitute almost 2% of human genes, regulate a vast map of cellular processes by mediating the phosphorylation of their substrates.[1]. The shrinkage of the PNIPAM backbone brought peptides closer, which may have enhanced the b-sheet structure and caused a slight blue shi ing, as indicated by the CD signal (Fig. S9c†), resulting in nano ber formation.[33] at a normal body temperature of approximately 37.5 C, P2 and P3 formed assemblies with drastically different nanomorphologies, which may result in differentiated biological activities (Vide infra). The higher concentration of P1-P and phosphorylation ratio could be ascribed to the over-expression of PKA in MCF-7 cells[23] (Fig. S16†).
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