Abstract
Leptin, an adipose tissue-derived hormone, exhibits potent tumor promoting effects through various mechanisms. Cathepsin B, a member of the lysosomal cysteine proteases, has been shown to modulate the growth of cancer cells. In this study, we have investigated the role of cathepsin B signaling in leptin-induced hepatic cancer growth. Leptin treatment caused significant increase in the levels of active cathepsin B through the axis of endoplasmic reticulum stress and autophagy induction without significant effects on pre- and pro-forms of cathepsin B. Interestingly, inhibition of cathepsin B signaling by gene silencing or treatment with a selective pharmacological inhibitor (CA-074) prevented leptin-enhanced viability of hepatic cancer cell and suppressed progression of cell cycle, indicating the critical role of cathepsin B in leptin-induced hepatic cancer growth. We have further observed that maturation of cathepsin B is required for NLRP3 inflammasomes activation, which is implicated in the growth of hepatic cancer cell. The crucial roles of cathepsin B maturation in leptin-induced hepatic cancer growth and NLRP3 inflammasomes activation were confirmed in an in vivo HepG2 tumor xenograft model. Taken together, these results demonstrate that cathepsin B signaling plays a pivotal role in leptin-induced hepatic cancer cell growth by activating NLRP3 inflammasomes.
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Acknowledgements
This work was supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF), funded by the Ministry of Education (NRF-2021R1A2C1013132) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2020R1A6A1A03044512). The authors thank the Ministry of Education and the Basic Science Research Program of the National Research Foundation of Korea (NRF) for financial support; the Core Research Support Center for Natural Products and Medical Materials (CRCNM) for the technical support regarding the confocal microscopic analysis.
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This work was supported by National research foundation of Korea (Grant Nos. NRF-2021R1A2C1013132, 2020R1A6A1A03044512).
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Nguyen, T., Kumar, R.P. & Park, PH. Cathepsin B maturation plays a critical role in leptin-induced hepatic cancer cell growth through activation of NLRP3 inflammasomes. Arch. Pharm. Res. 46, 160–176 (2023). https://doi.org/10.1007/s12272-023-01437-2
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DOI: https://doi.org/10.1007/s12272-023-01437-2