Cucurbitacin E Induces Autophagy-Involved Apoptosis in Intestinal Epithelial Cells

Abstract

Apoptosis plays a crucial role in maintaining the structural and functional integrity of the intestinal epithelial barrier. Autophagy mediates injury to and repair of the intestinal epithelial barrier through multiple pathways in pathophysiological conditions. Our earlier study has found that cucurbitacin E (CuE) regulates the proliferation, migration, and permeability of human intestinal epithelial cells (IECs); however, its effects and mechanisms on apoptosis and autophagy are still unclear. This study reported CuE induced apoptosis and promoted autophagy of IECs in a concentration-dependent manner. The results showed that CuE could inhibit the expression of apoptosis-related protein Bcl-2 and drove activation of caspase-3 and cleavage of its substrate poly (ADP-ribose) polymerase. CuE also facilitated the expression of endoplasmic reticulum stress-related proteins, CHOP and Grp78, and autophagy-related proteins, Beclin1 and LC3, while inhibiting the phosphorylation of AKT and mammalian target of rapamycin (mTOR). An autophagy inhibitor, 3-methyladenine, reduced CuE-induced apoptosis. These results suggest that CuE may induce apoptosis and autophagy in IECs via the PI3K/AKT/mTOR signaling pathway and that autophagy following endoplasmic reticulum stress participates in the pro-apoptotic process induced by CuE.

Investigation of apoptotic effects of Cucurbitacin D, I, and E mediated by Bax/Bcl‐xL, caspase‐3/9, and oxidative stress modulators in HepG2 cell line

“…Chemotherapeutic agents play a role as oxidants and regulate the mitochondrial apoptotic pathway by inducing ROS‐mediated activation of Fas ligand and TRAIL (Altinoz et al, 2022; Kim et al, 2008; Wang et al, 2008). Previous studies have reported that cucurbitacins exhibit anticancer effects by modulating apoptotic and autophagic signaling mechanisms through ROS induction (Kim et al, 2020; Luo et al, 2018; Ma et al, 2016; Song et al, 2020; Zhang & Li, Park, et al, 2012). CuD activates the ROS/p38 pathway and induces apoptosis in pancreatic cancer cells (Kim et al, 2020).…”

“…Cucurbitacins are natural compounds known for their antiproliferative activity in many types of cancer cells, lacking specific cell and tissue specificity (Chung et al, 2015). Studies have shown that cucurbitacins exert their anticancer properties by targeting multiple signaling pathways, including JAK/STAT3 (Üremiş et al, 2022b), Wnt/β‐catenin (Yang et al, 2020), MAPK (Üremiş et al, 2022b), PI3K/AKT/mTOR (Üremiş et al, 2022b), Ras/Raf/MEK/ERK (Chan et al, 2010), and autophagy (Song et al, 2020), rather than a single overactivated pathway in cancer. Furthermore, cucurbitacins exhibit potent cytotoxic effects at low concentrations, allowing for the reduction of therapeutic doses compared to conventional chemotherapeutic drugs used at high concentrations (Jing et al, 2020).…”

“…While cucurbitacins B and D are present in the highest concentrations in plants of the Cucurbitaceae family, cucurbitacins B, D, E, and I have been the most extensively studied for their anticancer, antioxidant, and anti‐inflammatory activities (Chung et al, 2015). Cucurbitacins have been stated to possess antitumor activity through a range of processes, for instance, inhibiting cell replication (Sikander et al, 2019), halting the cell cycle (Uremis et al, 2022b), inducing apoptosis (Üremiş et al, 2022b), restraining angiogenesis and metastasis (Hsu et al, 2019), and destruction of the protein skeleton and autophagy (Song et al, 2020).…”

Cucurbitacin E Exerts Anti-Proliferative Activity via Promoting p62-Dependent Apoptosis in Human Non-Small-Cell Lung Cancer A549 Cells

“…In addition to inducing apoptotic cell death, recent studies have demonstrated that Cu E can also promote autophagy by modulating key signaling pathways, such as the PI3K/Akt pathway and the mTOR signaling pathway [31,38]. To further investigate the effects of Cu E on autophagy in A549 cells, we examined the levels of regulatory proteins by Western blotting.…”

“…Several studies have investigated the effects of Cu E on autophagy, although its impact on cell death remains controversial. Some findings suggest that Cu E inhibits the PI3K/AKT/mTOR signaling pathway, leading to the activation of autophagy in human cancer cells and intestinal epithelial cells [31,38]. Conversely, Cu E has been found to induce protective autophagy mediated by ROS in lung 95D cells [39].…”