Pentagalloylglucose induces ferroptosis-related cell death by disrupting lipid homeostasis through the let-7a-5p/LIN28B/SREBP1 axis in colorectal cancer.
Abstract
Colorectal cancer (CRC) is characterized by metabolic reprogramming, including lipid accumulation, which promotes tumor progression and resistance to cell death. Although 1,2,3,4,6-penta-O-galloyl-β-D-glucose (PGG) has reported anticancer effects, its effects on lipid metabolism and ferroptosis-related cell death in CRC remain unclear. We investigated these effects in CRC cells and an MC38 syngeneic tumor model. PGG decreased triglyceride levels in three CRC cell lines, whereas cell viability decreased only in SW620 cells. In SW620 cells, PGG decreased lipid droplet accumulation and induced expression of let-7a-5p, a tumor-suppressive microRNA involved in lipid regulation. Lin-28 homolog B (LIN28B), a target of let-7a, regulates sterol regulatory element-binding transcription factor 1 (SREBP1)-associated lipogenic signaling. PGG and a let-7a-5p mimic reduced LIN28B and precursor and mature SREBP1 expression, along with downstream lipogenic protein expression. Both treatments also decreased glutathione and the ferroptosis-protective proteins solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), while increasing lipid peroxidation. The ferroptosis inhibitors ferrostatin-1, liproxstatin-1, and deferoxamine attenuated lipid peroxidation and the reduction in cell viability. LIN28B overexpression attenuated PGG-induced changes in SREBP1, SLC7A11, and GPX4 expression and lipid peroxidation. Similar changes in lipid metabolism and ferroptosis-related signaling were observed in MC38 cells. Oral PGG administration inhibited tumor growth in MC38 tumor-bearing mice. Intratumoral let-7a-5p expression increased, whereas triglyceride levels and LIN28B, SREBP1, SLC7A11, and GPX4 expression decreased. Collectively, these findings suggest that PGG alters lipid homeostasis through a pathway involving let-7a-5p, LIN28B, and SREBP1 and that ferroptosis-related lipid peroxidation contributes to its effects in responsive CRC cells.