Advances of Protein Palmitoylation in Tumor Cell Deaths

Abstract

In this comprehensive survey, we delve into the multifaceted role of palmitoylation across various cell death modalities in the oncological context, from its intricate correlations with tumorigenesis, steered by the Asp-His-His-Cys tetrapeptide motif (DHHC) family, to the counter-process of depalmitoylation mediated by enzymes like Palmitoyl protein thioesterase-1 (PPT1). Innovations in detection methodologies have paralleled our growing understanding, transitioning from rudimentary techniques to sophisticated modern methods. Central to our discourse are agents like Ezurpimtrostat (GNS561) and dimeric chloroquine (DC661), promising heralds in palmitoylation-targeted cancer therapy. Collectively, this review accentuates palmitoylation's transformative potential in oncology, foreshadowing groundbreaking therapeutic strategies and deepening our molecular comprehension of cancer dynamics.

Keywords: apoptosis; autophagy; ferroptosis; protein palmitoylation; pyroptosis.

Figure 1

Schematic representations of S-palmitoylation, O-palmitoylation, and N-palmitoylation reactions. The figure elucidates the enzymatic mechanisms underlying protein palmitoylation. Palmitoyltransferases (PATs) mediate the transfer of palmitate from palmitoyl-CoA to target proteins, marking S-palmitoylation as typically reversible. Conversely, O-palmitoylation and N-palmitoylation are shown as irreversible alterations. The figure further identifies PPTs as the enzymes that reverse S-palmitoylation, thereby enabling the dynamic control of this post-translational modification.

Figure 2

Palmitoylation in tumor apoptosis and cancer progression. The palmitoylation modification of proteins such as p53, BAX, and CD95 (Fas) plays a pivotal role in modulating apoptosis and influencing tumor progression. Proteins that undergo palmitoylation are denoted by a red spring.

Figure 3

Palmitoylation in autophagic signaling and cancer progression. It highlights the growing importance of PPT1 in the regulation of apoptosis, autophagy, and AKT phosphorylation. Moreover, it points to the therapeutic potential of PPT1 inhibitors, such as GNS561 and DC661, in treating various cancers. The intricate relationship between PPT1 and key cellular pathways opens up new prospects for innovative cancer therapies. In this context, ZDHHC3 functions as a palmitoyltransferase, while PPT1 acts as a depalmitoylating enzyme. Proteins undergoing palmitoylation, including AKT, IFNGR1, and PD-L1, are denoted by red springs.

Figure 4

Palmitoylation-modulated interplay of ferroptosis and pyroptosis in oncological contexts. Ferroptosis is closely associated with critical molecules such as SLC7A11, which affect glutathione synthesis and the activity of GPX4. Palmitoylation plays a crucial role in chemically induced pyroptosis by regulating the cleavage of Gasdermin proteins, leading to inflammatory responses. CD8+ T cells influence both pyroptosis and ferroptosis via the secretion of GzmA protein and the action of IFN-γ, respectively. This sophisticated interplay between cell death pathways and immune responses opens up potential strategies for novel cancer treatments, as demonstrated by the use of therapeutic agents like erianin. ZDHHCs, which are palmitoyltransferases, modify proteins such as SLC7A11, NLRP3, and GSDME through palmitoylation, depicted as red springs.