Novel strategies to improve tumour therapy by targeting the proteins MCT1, MCT4 and LAT1.

Poor selectivity, potential systemic toxicity and drug resistance are the main challenges associated with chemotherapeutic drugs. MCT1 and MCT4 and LAT1 play vital roles in tumour metabolism and growth by taking up nutrients and are thus potential targets for tumour therapy. An increasing number of studies have shown the feasibility of including these transporters as components of tumour-targeting therapy. Here, we summarize the recent progress in MCT1-, MCT4-and LAT1-based therapeutic strategies. First, protein structures, expression, relationships with cancer, and substrate characteristics are introduced. Then, different drug targeting and delivery strategies using these proteins have been reviewed, including designing protein inhibitors, prodrugs and nanoparticles. Finally, a dual targeted strategy is discussed because these proteins exert a synergistic effect on tumour proliferation. This article concentrates on tumour treatments targeting MCT1, MCT4 and LAT1 and delivery techniques for improving the antitumour effect. These innovative tactics represent current state-of-the-art developments in transporter-based antitumour drugs.

Selective autophagy receptor SQSTM1/ p62 inhibits Seneca Valley virus replication by targeting viral VP1 and VP3.

Macroautophagy/autophagy plays a critical role in antiviral immunity through targeting viruses and initiating host immune responses. The receptor protein, SQSTM1/p62 (sequestosome 1), plays a vital role in selective autophagy. It serves as a receptor targeting ubiquitinated proteins or pathogens to phagophores for degradation. In this study, we explored the reciprocal regulation between selective autophagy receptor SQSTM1 and Seneca Valley virus (SVV). SVV infection induced autophagy. Autophagy promoted SVV infection in pig cells but played opposite functions in human cells. Overexpression of SQSTM1 decreased viral protein production and reduced viral titers. Further study showed that SQSTM1 interacted with SVV VP1 and VP3 independent of its UBA domain. SQSTM1 targeted SVV VP1 and VP3 to phagophores for degradation to inhibit viral replication. To counteract this, SVV evolved strategies to circumvent the host autophagic machinery to promote viral replication. SVV 3Cpro targeted the receptor SQSTM1 for cleavage at glutamic acid 355, glutamine 392, and glutamine 395 and abolished its capacity to mediate selective autophagy. At the same time, the 3Cpro-mediated SQSTM1 cleavage products lost the ability to inhibit viral propagation. Collectively, our results provide evidence for selective autophagy in host against viruses and reveal potential viral strategies to evade autophagic machinery for successful pathogenesis.Abbreviations: Baf.A1: bafilomycin A1; Co-IP: co-immunoprecipitation; hpi: h post-infection; LIR: LC3-interacting region; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MOI: multiplicity of infection; PB1: N-terminal Phox/Bem1p; Rap.: rapamycin; Seneca Valley virus: SVV; SQSTM1/p62: sequestosome 1; SQSTM1-N355: residues 1 to 355 of SQSTM1; SQSTM1-C355: residues 355 to 478 of SQSTM1; SQSTM1-N392: residues 1 to 392 of SQSTM1; SQSTM1-C392: residues 392 to 478 of SQSTM1; SQSTM1-N388: residues 1 to 388 of SQSTM1; SQSTM1-N397: residues 1 to 397 of SQSTM1; UBA: ubiquitin association; Ubi: ubiquitin.