Chaetocin, a Natural Inhibitor of Transketolase, Suppresses the Non-Oxidative Pentose Phosphate Pathway and Inhibits the Growth of Drug-Resistant Non-Small Cell Lung Cancer

Worldwide, lung cancer is the most common cause of cancer-related death, which is made worse by the development of drug resistance during treatment. It is urgent to develop new therapeutic methods and small molecule drugs for tumor resistance. Chaetocin, extracted from <i>Chaetomium minutum</i>, is a natural compound with good antitumor activity. However, there are few studies on its tumor resistance. In this paper, firstly, chaetotocin significantly inhibited the viability and migration of cisplatin-resistant non-small cell lung cancer (NSCLC) cells and inhibited the xenograft growth of nude mice. Chaetocin at 4 mg/kg significantly inhibited A549/DDP xenograft growth with an inhibition rate of 70.43%. Subsequently, the underlying mechanism behind the actions of chaetocin was explored. It was discovered that chaetocin can inhibit transketolase (TKT), thereby inhibiting the growth of NSCLC cells and inducing cell death. Compared with cisplatin-sensitive cells, a lower concentration of chaetocin can inhibit cisplatin-resistance cell viability and migration. Mechanistically, TKT was identified as a potential target for chaetocin. The KD value of the interaction between chaetocin and TKT was 63.2 μM. An amount of 0.2 μM chaetocin may suppress the enzyme activity and expression level of TKT. We found the TKT expression is higher in cisplatin-resistant cells, which further explains why these cells were more vulnerable to chaetocin in terms of cell phenotype. Additionally, the muti-omics analysis and RNA interference suggested that chaetocin can inhibit the PI3K/Akt signaling pathway through TKT. In conclusion, chaetocin could directly bind to TKT, inhibiting its enzyme activity and expression, which interfered with intracellular metabolism and oxidation-reduction balance, and then regulated the PI3K/Akt signaling pathway to inhibit the growth of NSCLC and induce apoptosis.