Nobiletin inhibits non-small cell lung cancer through TRKC and exhibits a synergistic effect with HDAC inhibitor

Approximately 85% of all lung cancer cases are classified as non-small cell lung cancer (NSCLC). Given its poor prognosis and tendency to resist radiotherapy and chemotherapy, there is an urgent need to explore its molecular mechanisms to develop novel and more effective therapeutic approaches. In prior research, we identified nobiletin from a compound library and confirmed that it acts as a novel natural BH3 mimetic. Nobiletin synergized with vorinostat to induce autophagy and apoptosis in small-cell lung cancer. In the current investigation, we further discovered that nobiletin, either alone or in combination with vorinostat, exerts inhibitory effects on NSCLC. Specifically, the combination of nobiletin and vorinostat inhibited the proliferation of NSCLC A549 cells. Nobiletin, whether used alone or in combination with vorinostat, can induce apoptosis in A549 cells by mimicking the action of BH3-only proteins. This included downregulating the expression of anti-apoptosis proteins such as BCL-2 and MCL-1, upregulating the expression of apoptosis-related proteins Cleaved-Caspase 3 and Cleaved-PARP, and increasing the expression of BH3-only protein. Nobiletin binding to BCL-2 facilitates the dissociation of the Beclin-1/BCL-2 complex, thereby increasing the levels of free Beclin-1. Furthermore, the combination with nobiletin and vorinostat enhances the expression of LC3A/BII and FOXO1, ultimately inducing autophagy in A549 cells. Eukaryotic transcriptome sequencing demonstrated that the combination treatment primarily inhibits tumor cell proliferation by modulating TRKC protein expression, suppressing the phosphorylation of the PI3K/AKT/mTOR signaling pathway. Therefore, our results indicate that nobiletin, a natural BH3 mimetic compound, synergizes with vorinostat to affect NSCLC apoptosis and autophagy.