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 (cis-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 in vivo and in vitro. 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.