Downregulated CCND3 Is a Key Event Driving Lung Adenocarcinoma Metastasis during Acquired Cisplatin Resistance

Cyclin D3 (CCND3), a member of the cyclin D family, is known to promote cell cycle transition. In this study, we found that CCND3 was downregulated in cisplatin-resistant (<i>cis</i>-diamminedichloroplatinum, DDP) lung adenocarcinoma (LUAD) cells. The loss of CCND3 indeed impeded cell cycle transition. Unexpectedly, its downregulation significantly triggered cytoskeleton remodeling and chemoresistance and accelerated LUAD metastasis <i>in vivo</i> and <i>in vitro</i>. Moreover, the clinical samples showed a significant negative correlation between CCND3 expression and lymphatic metastasis, as well as the unfavorable survival prognosis of patients with LUAD. Mechanistically, CCND3 downregulation in DDP-resistant LUAD cells was attributable to the transcriptional suppression of PI3K/Akt/c-Jun signaling. Reduced CCND3 expression diminished the recruitment of the E3 ubiquitin ligase PARK2 to ubiquitinate and degrade the vimentin protein, thus triggering epithelial-mesenchymal transition (EMT) to result in cytoskeleton remodeling-stimulated metastasis and chemotherapeutic resistance in LUAD. These results demonstrated that activated PI3K/Akt/c-Jun significantly suppressed CCND3 expression, thereby inhibiting vimentin degradation via PARK2-mediated ubiquitination in DDP-resistant LUAD cells. This, in turn, promoted EMT, facilitating cytoskeleton remodeling-stimulated metastasis and chemoresistance to DDP. Overall, these findings provided a new perspective on the role of CCND3 in LUAD progression and acquired cisplatin resistance.