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. 2023 Mar;46(3):160-176.
doi: 10.1007/s12272-023-01437-2. Epub 2023 Mar 11.

Cathepsin B maturation plays a critical role in leptin-induced hepatic cancer cell growth through activation of NLRP3 inflammasomes

ThiKem Nguyen #  1 , Raut Pawan Kumar #  1 , Pil-Hoon Park  2   3
Affiliations

Cathepsin B maturation plays a critical role in leptin-induced hepatic cancer cell growth through activation of NLRP3 inflammasomes

ThiKem Nguyen et al. Arch Pharm Res. 2023 Mar.

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.

Keywords: Autophagy; Cathepsin B; ER stress; Inflammasomes; Leptin.

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