Harmine inhibits breast cancer cell migration and invasion by inducing the degradation of Twist1

Abstract

Breast cancer is the leading cause of cancer-related deaths in the United States. The majority of deaths (90%) in breast cancer patients is caused by invasion and metastasis–two features related to the epithelial-to-mesenchymal transition (EMT). Twist1 is a key transcription factor that promotes the EMT, which leads to cell migration, invasion, cancer metastasis, and therapeutic resistance. Harmine is a beta-carboline alkaloid found in a variety of plants and was recently shown to be able to induce degradation of Twist Family BHLH Transcription Factor 1 (Twist1) in non-small cell lung cancer cells (NSCLC). In this study, we show that harmine can inhibit migration and invasion of both human and mouse breast cancer cells in a dose-dependent manner. Further study shows that this inhibition is most likely achieved by inducing a proteasome-dependent Twist1 degradation. At the concentrations tested, harmine did not affect the viability of cells significantly, suggesting that its inhibition of cancer cell migration and invasion is largely independent of its cytotoxicity, but due to its ability to affect regulators of EMT such as Twist1. This result may facilitate the development of strategies that target Twist1 to treat metastatic breast cancer, as Twist1 is expressed at a high level in metastatic breast cancer cells but not in normal cells.

Activation of endoplasmic reticulum stress by harmine suppresses the growth of esophageal squamous cell carcinoma

“…In recent years, harmine has been reported to elicit a series of anti‐cancer activities, but the detailed mechanism remains obscure (Dai et al, 2012; He et al, 2022; Nafie et al, 2021; Uhl et al, 2018; Wu et al, 2019; Zhang et al, 2014; Zhu et al, 2021). In this study, we report that harmine can activate ER stress, resulting in the up‐regulation of DR5 and SESN2, which promotes apoptosis and autophagosome formation in KYSE‐30 and EC‐9706 cells, respectively (Figure 9).…”

“…Several studies have demonstrated that harmine and its derivatives exhibit anti‐cancer activities via the regulation of cyclooxygenase‐2, Twist1, FAK/Akt, p53, and MAPK, among other pathways (Dai et al, 2012; Nafie et al, 2021; Ock & Kim, 2021; Zhang et al, 2014; Zhu et al, 2021). In KYSE‐30 and EC‐9706 cells, harmine down‐regulated the phosphorylation of AMPK, Akt, and mTOR (Figure 6), which are downstream targets of SESN2 and play key roles in regulating autophagic responses (Ibanez‐Cabellos et al, 2018; Kma & Baruah, 2022).…”

“…β‐carboline alkaloids are a remarkable family of natural and synthetic alkaloids with diverse pharmacological activities (Byun et al, 2022; Poje et al, 2022; Wu et al, 2020). Harmine, a classical small molecule β‐carboline alkaloid (Figure 1a), is known for its biological and anti‐cancer activities and has received a great deal of interest in cancer research (Dai et al, 2012; He et al, 2022; Nafie et al, 2021; Uhl et al, 2018; Wu et al, 2019; Zhang et al, 2014; Zhu et al, 2021).…”

Recent advances in BCRP‐induced breast cancer resistance treatment with marine‐based natural products

“…Harmine inhibits the growth of different cancer cell types (e.g., ovarian and gastric cancer). 95 It is able to prevent tumor development, metastasis, and triggering apoptosis and possess anti-cancer capabilities. The pharmacological effects of harmine include antifungal, antibacterial, antiplasmodial, antioxidant, cytotoxic, antitumoral, hallucinogenic and antimutagenic action.…”

“…A beta‐carboline alkaloid (Figure 4) with a wide dissemination in nature is called as harmine. Harmine inhibits the growth of different cancer cell types (e.g., ovarian and gastric cancer) 95 . It is able to prevent tumor development, metastasis, and triggering apoptosis and possess anti‐cancer capabilities.…”