Cyclin C Suppresses Pancreatic Intraepithelial Neoplasia and Neural Endocrine Neoplasia Progression in a Murine Kras Model.

Cyclin C is a component of the Cdk8 kinase module that plays both a positive and negative role in transcription. In addition, cellular damage induces cyclin C re-localization to the mitochondria where it stimulates fission and recruits Bax in preparation for apoptotic initiation. Previous studies revealed that cyclin C suppresses thyroid hyperplasia in a Pten knockout mouse model. In the present study, a role for cyclin C in suppressing pancreatic cancer progression was investigated in the LSL-Kras murine cancer model. Within eight weeks, a 6-8 fold increase in the appearance of pancreatic Intraepithelial neoplasia (PanIN) and acinar ductal metaplasia (ADM) lesions were observed in the Kras ; Ccnc animals compared to Kras alone. Surprisingly, high-grade, poorly differentiated pancreatic neuroendocrine tumors/carcinomas (PNET/PNEC) were also observed. These lesions coexisted in the pancreas with some PanIN regions possessing intermixed cells expressing PNEC markers. Our previous studies identified a positive role for cyclin C in autophagy gene transcription. Similarly, cell lines derived from a Kras ; Ccnc pancreas exhibited a reduction in autophagy compared to Kras ; Ccnc cells. Autophagic deficiency induces pancreatic cell stress and is associated with elevated apoptosis. Consistent with this model, caspase 3 activation was observed in early Kras ; Ccnc PNETs but not in Kras tissues. In addition, Kras ; Ccnc cells showed decreased proteasomal activity and a 30% increase in cell death compared to Kras ; Ccnc cells following treatment with the proteasome inhibitor, Bortezomib. Taken together, these results demonstrate a role for cyclin C in suppressing both PDAC and PNEN cancer progression and suggest a model that its loss promotes pre-cancerous lesions by stimulating pancreatic cell injury.