RETRACTED: Resibufogenin suppresses growth and metastasis through inducing caspase‐1‐dependent pyroptosis via ROS‐mediated NF‐κB suppression in non‐small cell lung cancer

Abstract

The purpose of this study is to explore the antitumor properties of resibufogenin (RB) in non‐small cell lung cancer (NSCLC) and elucidate its underlying mechanism. A549 and H520 cells were treated with various concentrations of RB with or without NLRP3 inhibitor (MCC950), caspase‐1 inhibitor (VX765), or N‐acetyl‐l‐cysteine (an ROS scavenger). Cell counting kit‐8 and colony formation assays were conducted to determine cell viability. Cell invasion was detected by using the transwell assay. The release of lactate dehydrogenase (LDH) was determined by the LDH detection assay. The protein expression levels of related genes were measured by western blotting and immunohistochemistry. The reactive oxygen species (ROS) level was detected by using a 2,7‐dichlorodihydrofluorescein diacetate ROS Assay Kit. The in vivo effects of RB were evaluated in a xenograft mouse model. RB treatment reduced cell viability and invasion in a dose‐dependent manner. Furthermore, RB also enhanced pyroptosis levels in A549 and H520 cells, as indicated by the increased release of LDH and pyroptosis‐related proteins. Interestingly, we also found that the antiproliferative and antimetastatic effects of RB were alleviated by the blockade of pyroptosis using NLRP3 inhibitor MCC950. Further study demonstrated that RB induced pyroptosis in a caspase‐1‐dependent manner, as evidenced by the finding that VX765 effectively reversed the effects of RB on A549 and H520 cells. We also found that RB could trigger caspase‐1‐dependent pyroptosis through ROS‐mediated NF‐κB suppression. In summary, our findings provide a potential antitumor agent and a novel insight into the mechanism of RB treatment of NSCLC.

Induction of Pyroptosis: A Promising Strategy for Cancer Treatment

“…Thus, the role of NF-kB remains elusive. Additionally, Resibufogenin was found to suppress metastasis by caspase-1 activation, which is manifested as downregulated MMP-2, downregulated MMP-9 and upregulated TIMP-3, further strengthening its antitumor effect (58). P53 was also involved in the regulation of NSCLC canonical pyroptosis.…”

“…Highly expressed GSDMD also improved the possibility to eliminate tumors through the canonical pyroptosis pathway. In recent years, several substances, including 4hydroxybenacid, Simvastatin, huaier extract, polyphyllin VI, Resibufogenin, have been proved to kill NSCLC via caspase-1dependent pyroptosis (54)(55)(56)(57)(58). Polyphyllin VI could elevate ROS/ NF-kB signaling to activate canonical pyroptosis in A549 and H1299 cell lines.…”

“…Thus, regulating NF-kB activity becomes an important strategy for cancer therapy. Resibufogenin, L61H10, JQ1 and other drugs can activate pyroptosis via inhibiting NF-kB (58,63,103). However, Polyphyllin VI and Casticin were reported to activate NF-kB and caspase-1-dependent pyroptosis (57,105).…”

Non-coding RNAs in necroptosis, pyroptosis and ferroptosis in cancer metastasis

“…FL118 activated NLRP3-ASC-Caspase-1-mediated pyroptosis, which suppressed the metastasis of colorectal cancer cells [ 60 ]. Moreover, resibufogenin triggers caspase-1-dependent pyroptosis through ROS-mediated NF-kappaB suppression to inhibit metastasis of non-small cell lung cancer [ 61 ]. Secondly, pyroptosis provides a suitable microenvironment for tumor growth to exert the role of pro-inflammatory cell death.…”

CD147 Aggravated Inflammatory Bowel Disease by Triggering NF-κB-Mediated Pyroptosis

“…An LDH assay was performed as described in Yin et al's study [ 28 ]. The levels of LDH were determined by using the LDH Release Assay Kit (Beyotime, Shanghai, China) according to the manufacturer's protocol.…”