Lycorine promotes IDH1 acetylation to induce mitochondrial dynamics imbalance in colorectal cancer cells

Isocitrate dehydrogenase (IDH) 1 and 2, as essential enzymes in energy metabolism, contribute to the survival and drug resistance of a variety of solid tumors, especially for colorectal cancer (CRC). However, the underlying molecular mechanism still remains unclear. In this study, IDH1 was identified as a crucial cellular target of a natural-derived anti-CRC small molecule lycorine, using the unbiased thermal proteome profiling (TPP) strategy. We found that lycorine directly targeted a unique C-terminal domain of IDH1, and disrupted IDH1 interaction with deacetylase sirtuin 1 (SIRT1), thereby significantly promoting IDH1 acetylation modification. Then, lycorine noticeably triggered oxidative stress in CRC cells to cause mitochondrial membranes injury, and subsequently facilitated mitochondrial fission. Specific knockdown of IDH1 or SIRT1 markedly aggrieved lycorinemediated oxidative stress and mitochondrial fragmentation in CRC cells. Furthermore, the combination of lycorine and sirtuins blocker nicotinamide (NAM) exhibited a synergic therapeutic effect in CRC cells. Collectively, our results reveal that IDH1 may serve as a promising therapeutic target for CRC via pharmacologically driving oxidative stress-dependent mitochondrial dynamics imbalance.

Automated summary

In this study, it was found that the natural-derived anti-colorectal cancer small molecule lycorine targets a unique C-terminal domain of IDH1, disrupting its interaction with SIRT1 and promoting IDH1 acetylation modification, resulting in oxidative stress and mitochondrial dynamics imbalance in CRC cells. Knockdown of IDH1 or SIRT1 aggravated these effects, while the combination of lycorine and NAM showed a synergic therapeutic effect in CRC cells.