Hispidin induces autophagic and necrotic death in SGC-7901 gastric cancer cells through lysosomal membrane permeabilization by inhibiting tubulin polymerization

Abstract

Hispidin and its derivatives are widely distributed in edible mushrooms. Hispidin is more cytotoxic to A549, SCL-1, Bel7402 and Capan-1 cancer cells than to MRC5 normal cells; by contrast, hispidin protects H9c2 cardiomyoblast cells from hydrogen peroxide-induced or doxorubicin-induced apoptosis. Consequently, further research on how hispidin affects normal and cancer cells may help treat cancer and reduce chemotherapy-induced side effects. This study showed that hispidin caused caspase-independent death in SGC-7901 cancer cells but not in GES-1 normal cells. Hispidin-induced increases in LC3-II occurred in SGC-7901 cells in a time independent manner. Cell death can be partially inhibited by treatment with ATG5 siRNA but not by autophagy or necroptosis inhibitors. Ultrastructural evidence indicated that hispidin-induced necrotic cell death involved autophagy. Hispidin-induced lysosomal membrane permeabilization (LMP) related to complex cell death occurred more drastically in SGC-7901 cells than in GES-1 cells. Ca2+ rather than cathepsins from LMP contributed more to cell death. Hispidin induced microtubule depolymerization, which can cause LMP, more drastically in SGC-7901 cells than in GES-1 cells. At 4.1 μM, hispidin promoted cell-free tubulin polymerization but at concentrations higher than 41 μM, hispidin inhibited polymerization. Hispidin did not bind to tubulin. Alterations in microtubule regulatory proteins, such as stathmin phosphorylation at Ser16, contributed to hispidin-induced SGC-7901 cell death. In conclusion, hispidin at concentrations higher than 41 μM may inhibit tubulin polymerization by modulating microtubule regulatory proteins, such as stathmin, causing LMP and complex SGC-7901 cell death. This mechanism suggests a promising novel treatment for human cancer.

Screening for Proteins Related to The Biosynthesis of Hispidin and Its Derivatives in Phellinus Igniarius Using iTRAQ Proteomic Analysis

“…The present study demonstrates that 3 mg/g hispidin-enriched fungus mycelia has a very low order of toxicity, which supports its safety for human consumption [17]. Therefore, HIP has attracted quite a lot of attention in the elds of chemistry, pharmacy and microbiology [18][19][20][21].…”

Derrone induces autophagic cell death through induction of ROS and ERK in A549 cells

“…In addition, DR increased the Ca 2+ concentration in the cytoplasm in a second (Fig 5A and 5B), and BAPTA-AM, an intracellular Ca 2+ chelator, significantly inhibited DR-induced formation of cytoplasmic vacuoles as well as reduction of MMP (Fig 5C and 5E). Although there have been several previous studies showing that cytoplasmic Ca 2+ overload induces autophagy [26, 27], the detailed mechanism of DR-induced autophagy associated with Ca 2+ need to be further explored. Finally, noteworthy is that prolonged activation of ERK signaling is required for DR-induced autophagy induction in A549 cells (Fig 6A).…”

Anticancer effect of YWHAZ silencing via inducing apoptosis and autophagy in gastric cancer cells

“…A recent study showed that activation of dopamine receptor D5 suppressed GC cells by inducing autophagic cell death [24]. More recent reports demonstrated that induction of autophagy inhibited GC cells proliferation [25][26][27]. However, research has also suggested that silencing AQP3 induces GC cell apoptosis by inhibiting autophagy [28].…”