Itch and autophagy-mediated NF-κB activation contributes to inhibition of cathepsin D-induced sensitizing effect on anticancer drugs

• Published in: Cell death & disease Vol. 13; no. 6; p. 552
• Main Authors: Seo, Seung Un, Woo, Seon Min, Min, Kyoung-jin, Kwon, Taeg Kyu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17-06-2022; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/1; 13/31; 13/89; 14/19; 38/77; 631/67/1059/99; 631/80/458/582; 631/80/82/39; Antibodies; Antineoplastic Agents - pharmacology; Antineoplastic drugs; Antitumor agents; Apoptosis; Autophagy; Bcl-x protein; Biochemistry; Biomedical and Life Sciences; Cancer; Cathepsin D; Cathepsin D - genetics; Cell Biology; Cell Culture; Chloroquine; Degradation; I-kappa B Proteins - metabolism; Immunology; Kinases; Life Sciences; LKB1 protein; NF-kappa B - metabolism; NF-κB protein; Signal transduction; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-022-05011-4

Inhibition of cathepsin D (Cat D) sensitizes cancer cells to anticancer drugs via RNF183-mediated downregulation of Bcl-xL expression. Although NF-κB activation is involved in the upregulation of RNF183 expression, the molecular mechanism of NF-κB activation by Cat D inhibition is unknown. We conducted this study to investigate the molecular mechanism underlying Cat D-mediated NF-κB activation. Interestingly, Cat D inhibition-induced IκB degradation in an autophagy-dependent manner. Knockdown of autophagy-related genes (
ATG7
and
Beclin1
) and lysosome inhibitors (chloroquine and bafilomycin A1) blocked IκB degradation via Cat D inhibition. Itch induced K63-linked ubiquitination of IκB and then modulated the protein stability of IκB by Cat D inhibition. Inhibition of Cat D-mediated Itch activation was modulated by the JNK signaling pathway, and phosphorylated Itch could bind to IκB, resulting in polyubiquitination of IκB. Additionally, inhibition of Cat D increased autophagy flux via activation of the LKB1-AMPK-ULK1 pathway. Therefore, our results suggested that Cat D inhibition activated NF-κB signaling via degradation of autophagy-dependent IκB, which is associated with the upregulation of RNF183, an E3 ligase of Bcl-xL. Cat D inhibition enhances TRAIL-induced apoptosis through Bcl-xL degradation via upregulation of RNF183.