8/12/2023 0 Comments Chaperone mediated autophagy 2019Furthermore, 922 could enhance chaperone-mediated autophagy (CMA) activity and promote the association between HSP/HSC70 and IGF-1Rβ or LAMP2A in coimmunoprecipitation and immunofluorescence analyses. However, knockdown of the crucial autophagy component AGT5 and the chemical inhibitor 3 MA-blocked 922-induced autophagy did not abrogate 922-triggered IGF-1Rβ degradation. Interestingly, 922 induced autophagic flux by increasing LC3II expression and puncta formation. These results might be associated with the inhibition of pancreatic cellular chymotrypsin–peptidase activity by 922 for 24 h. Preincubation with a proteasome or lysosome inhibitor (MG132, 3 MA or CQ) mainly led to IGF-1Rβ degradation via the lysosome degradation pathway, rather than the proteasome-dependent pathway, after PC cells were treated with 922 for 24 h. We found that the HSP90α inhibitor NVP-AUY922 (922) effectively downregulated and destabilized the IGF-1Rβ protein, substantially reduced the levels of downstream signaling molecules (p-AKT, AKT and p-ERK1/2), and resulted in growth inhibition and apoptosis in IGF-1Rβ-overexpressing PC cells. However, very little is known about how IGF-IR protein levels are degraded by HSP90 inhibitors in pancreatic cancer (PC). Enhancement of insulin-like growth factor 1 receptor (IGF-IR) degradation by heat shock protein 90 (HSP90) inhibitor is a potential antitumor therapeutic strategy.
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