Photothermal therapy( PTT) is an extremely promising tumor therapeutic modality.H owever,e xcessive heat inevitably injures normal tissues near tumors,a nd the damage to cancer cells caused by mild hyperthermia is easily repaired by stress-induced heat shock proteins (HSPs). Thus, maximizing the PTT efficiency and minimizing the damage to healthy tissues simultaneously by adopting appropriate therapeutic temperatures is imperative.H erein, an innovative strategy is reported:f erroptosis-boosted mild PTT based on as ingle-atom nanozyme (SAzyme). The Pd SAzyme with atom-economical utilization of catalytic centers exhibits peroxidase (POD) and glutathione oxidase (GSHOx) mimicking activities,a nd photothermal conversion performance,w hich can result in ferroptosis featuring the up-regulation of lipid peroxides (LPO) and reactive oxygen species (ROS). The accumulation of LPO and ROSprovides apowerfulapproach for cleaving HSPs,which enables Pd SAzyme-mediated mildtemperature PTT.
Nuclear translocation of SMAD2/3, core transcription factors of TGFβ signaling, is critical for hepatic stellate cell (HSC) differentiation into metastasis-promoting myofibroblasts. SMAD2/3 have multiple coactivators, including WW domain-containing transcription regulator protein 1 (WWTR1 or TAZ) and p300 acetyltransferase. In the nucleus, TAZ binds to SMAD2/3 to prevent SMAD2/3 nuclear export. However, how TAZ and SMAD2/3 enter the nucleus remains poorly understood because neither contains a nuclear localization signal (NLS), an amino acid sequence tagging proteins for nuclear transport. P300 is a NLS-containing large scaffold protein so we hypothesized that SMAD2/3 and TAZ may undergo nuclear import through complexing with p300. Coimmunoprecipitation, immunofluorescence, and nuclear fractionation assays revealed that TGFβ1 promoted binding of SMAD2/3 and TAZ to p300 and that p300 inactivation disrupted TGFβ1-mediated SMAD2/3 and TAZ nuclear accumulation. Deleting the p300 NLS blocked TGFβ1-induced SMAD2/3 and TAZ nuclear transport. Consistently, p300 inactivation suppressed TGFβ1-mediated HSC activation and transcription of genes encoding tumor-promoting factors, such as CTGF, TNC, POSTN, PDGFC, and FGF2, as revealed by microarray analysis. ChIP-qPCR showed that canonical p300-mediated acetylation of histones also facilitated transcription in response to TGFβ1 stimulation. Interestingly, although both TGFβ1- and stiffness-mediated HSC activation require p300, comparison of gene expression datasets revealed that transcriptional targets of TGFβ1 were distinct from those of stiffness-p300 mechanosignaling. Lastly, in tumor/HSC coinjection and intrasplenic tumor injection models, targeting p300 of activated-HSC/myofibroblasts by C646, shRNA, or cre-mediated gene disruption reduced tumor and liver metastatic growth in mice. Conclusion: P300 facilitates TGFβ1-stimulated HSC activation by both non-canonical (cytoplasm-to-nucleus shuttle for SMAD2/3 and TAZ) and canonical (histone acetylation) mechanisms. P300 is an attractive target for inhibiting HSC activation and the prometastatic liver microenvironment.
TGFβ induces the differentiation of hepatic stellate cells (HSCs) into tumor‐promoting myofibroblasts but underlying mechanisms remain incompletely understood. Because endocytosis of TGFβ receptor II (TβRII), in response to TGFβ stimulation, is a prerequisite for TGF signaling, we investigated the role of protein diaphanous homolog 1 (known as Diaph1 or mDia1) for the myofibroblastic activation of HSCs. Using shRNA to knockdown Diaph1 or SMIFH2 to target Diaph1 activity of HSCs, we found that the inactivation of Diaph1 blocked internalization and intracellular trafficking of TβRII and reduced SMAD3 phosphorylation induced by TGFβ1. Mechanistic studies revealed that the N‐terminal portion of Diaph1 interacted with both TβRII and Rab5a directly and that Rab5a activity of HSCs was increased by Diaph1 overexpression and decreased by Diaph1 knockdown. Additionally, expression of Rab5aQ79L (active Rab5a mutant) increased whereas the expression of Rab5aS34N (inactive mutant) reduced the endosomal localization of TβRII in HSCs compared to the expression of wild‐type Rab5a. Functionally, TGFβ stimulation promoted HSCs to express tumor‐promoting factors, and α‐smooth muscle actin, fibronection, and CTGF, markers of myofibroblastic activation of HSCs. Targeting Diaph1 or Rab5a suppressed HSC activation and limited tumor growth in a tumor implantation mouse model. Thus, Dipah1 and Rab5a represent targets for inhibiting HSC activation and the hepatic tumor microenvironment.
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