Oncogenic activation of KRAS and its surrogates is essential for tumour cell proliferation and survival, as well as for the development of protumourigenic microenvironments. Here, we show that the deubiquitinase USP12 is commonly downregulated in the KrasG12D-driven mouse lung tumour and human non-small cell lung cancer owing to the activation of AKT-mTOR signalling. Downregulation of USP12 promotes lung tumour growth and fosters an immunosuppressive microenvironment with increased macrophage recruitment, hypervascularization, and reduced T cell activation. Mechanistically, USP12 downregulation creates a tumour-promoting secretome resulting from insufficient PPM1B deubiquitination that causes NF-κB hyperactivation in tumour cells. Furthermore, USP12 inhibition desensitizes mouse lung tumour cells to anti-PD-1 immunotherapy. Thus, our findings propose a critical component downstream of the oncogenic signalling pathways in the modulation of tumour-immune cell interactions and tumour response to immune checkpoint blockade therapy.
TGF-β RI Kinase Inhibitor VI, SB431542, TGF-β RI Kinase Inhibitor VI, SB431542, CAS 301836-41-9, is a cell-permeable inhibitor of SMAD2 phosphorylation. Inhibits the activity of ALK4 and ALK5 (IC50 = 140 nM and 94 nM, respectively).
Collagenasi, 0.2 μm filtered, suitable for release of physiologically active rat hepatocytes, Type IV-S, 0.5-5.0 FALGPA units/mg solid, ≥125 CDU/mg solid
Agarosio funzionalizzato con proteina G, ad alta scorrevolezza, Protein G Agarose, Fast Flow suitable for medium and low pressure chromatography of IgG from mouse, sheep, and rabbit, and for immunoprecipitations.
Smad3 Inhibitor, SIS3, Smad3 Inhibitor, SIS3, CAS 1009104-85-1, is a cell-permeable, selective inhibitor of TGF-β1-dependent Smad3 phosphorylation and Smad3-mediated signaling. Does not affect Smad2, MAPK, ERK, or PI3-K.
JNK Inhibitor II, JNK Inhibitor II. SP600125, CAS 129-56-6, is a potent, cell-permeable, selective, and ATP competitive inhibitor of c-Jun N-terminal kinase (JNK; IC50 = 40 nM for JNK-1 & JNK-2 & 90 nM for JNK-3).
STAT3 Inhibitor III, WP1066, STAT3 Inhibitor III, WP1066, CAS 857064-38-1, is a cell-permeable AG490 tyrphostin analog that acts as a STAT3 pathway inhibitor. A potent anti-tumor agent.
SB 203580, Hydrochloride, SB 203580, Hydrochloride, CAS 869185-85-3, is a water-soluble form of SB 203580. A highly potent, selective, ATP-competitive inhibitor of p38 MAP Kinase (IC50 = 34 nM in vitro, 600 nM in cells).
