Correction of the tumor suppressor Salvador homolog-1 deficiency in tumors by lycorine as a new strategy in lung cancer therapy

Abstract

Salvador homolog-1 (SAV1) is a tumor suppressor required for activation of the tumor-suppressive Hippo pathway and inhibition of tumorigenesis. SAV1 is defective in several cancer types. SAV1 deficiency in cells promotes tumorigenesis and cancer metastasis, and is closely associated with poor prognosis for cancer patients. However, investigation of therapeutic strategies to target SAV1 deficiency in cancer is lacking. Here we found that the small molecule lycorine notably increased SAV1 levels in lung cancer cells by inhibiting SAV1 degradation via a ubiquitin-lysosome system, and inducing phosphorylation and activation of the SAV1-interacting protein mammalian Ste20-like 1 (MST1). MST1 activation then caused phosphorylation, ubiquitination, and degradation of the oncogenic Yes-associated protein (YAP), therefore inhibiting YAP-activated transcription of oncogenic genes and tumorigenic AKT and NF-κB signal pathways. Strikingly, treating tumor-bearing xenograft mice with lycorine increased SAV1 levels, and strongly inhibited tumor growth, vasculogenic mimicry, and metastasis. This work indicates that correcting SAV1 deficiency in lung cancer cells is a new strategy for cancer therapy. Our findings provide a new platform for developing novel cancer therapeutics.

Lycorine ameliorates isoproterenol-induced cardiac dysfunction mainly via inhibiting inflammation, fibrosis, oxidative stress and apoptosis

“…Numerous studies have explored the anti-tumor activity of LYC, including against cancers such as colorectal, gastric, bladder, lung, breast, melanoma, multiple myeloma, osteosarcoma, and hematological malignancies. The molecular mechanism of the anti-tumor activity of LYC is mainly attributed to the selective induction of apoptosis in cancer cells [13][14][15][16][17][18][19][20][21].…”

“…Lycorine (LYC), one component of Amaryllidaceae, is an alkaloid that displays various beneficial functions in some disease models, including anti-inflammation, anti-fibrosis, antiviral, anti-aging, and anti-tumor effects [8][9][10][11][12]. Recently, numerous studies focused on investigating the antitumor feature of LYC in colorectal cancer, gastric cancer, bladder cancer, lung cancer, breast cancer, melanoma, multiple myeloma, osteosarcoma, hematological malignancies [13][14][15][16][17][18][19][20][21]. After administration of LYC, cancer cells died selectively in large numbers because of apoptosis [21].…”

Molecular Insights into Tumor Targeted Therapy by Carrier-Free Lycorine Nanoparticles in Vitro and in Vivo

“…In our previous research, we found that Ly has a wide range of anti-tumor activities including apoptosis, autophagy, proliferation and so on [36][37][38]. In this study, we intend to compare whether DS-Ly NPs has better anti-tumor effects than Ly.…”

Lycorine, an isoquinoline alkaloid, inhibits breast cancer proliferation and metastasis involving cytoskeletal protein

“…Lycorine inhibits the growth and metastasis of various types of cancers, such as non-small cell lung cancer (Li et al, 2019), glioblastoma multiforme (Shen et al, 2018), lung cancer (Zhao et al, 2020), gastric cancer (Li et al, 2020). The previous review has testi ed that lycorine inhibited the growth and metastasis of breast cancer cells by inhibition of protein biosynthesis and the STAT3 and the Src/FAK signaling pathway (Wang et al, 2017).…”