(505.31) Cyclin C Suppresses Pancreatic Intraepithelial Neoplasia and Neural Endocrine Neoplasia Progression in a Murine Kras Model

Poster Board Number: A295

Sara Hanley (Rowan School of Osteopathic Medicine), Kathy Cai (Fox Chase Cancer Center), David Stieg (Rowan School of Osteopathic Medicine, Rowan School of Osteopathic Medicine), Andre-Klein Santos (Fox Chase Cancer Center), Kerry Campbell (Fox Chase Cancer Center), Randy Strich (Rowan School of Osteopathic Medicine)

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-KrasG12D 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 KrasG12D+; Ccnc-/- animals compared to KrasG12D 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 KrasG12D+; Ccnc-/- pancreas exhibited a reduction in autophagy compared to KrasG12D+; 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 KrasG12D+; Ccnc-/- PNETs but not in KrasG12D+ tissues. In addition, KrasG12D+; Ccnc-/- cells showed decreased proteasomal activity and a 30% increase in cell death compared to KrasG12D+; 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.

Support or Funding Information

This work was supported by grants from the National Institutes of Health awarded to R.S. (GM113052) and FCCC Comprehensive Cancer Center Support Grant (CA06927) in support of the Histopathology, Cell Culture, Laboratory Animal, and Genomics Facilities at FCCC. Additional support was provided by the Boye Foundation and the New Jersey Health Foundation (to R.S.) and from the Martin and Concetta Greenberg Pancreatic Cancer Institute at FCCC and Pennsylvania DOH Health Research Formula Funds (to K.S.C.).

lt;pgt;This work was supported by grants from the National Institutes of Health awarded to R.S. (GM113052) and FCCC Comprehensive Cancer Center Support Grant (CA06927) in support of the Histopathology, Cell Culture, Laboratory Animal, and Genomics Facilities at FCCC. Additional support was provided by the Boye Foundation and the New Jersey Health Foundation (to R.S.) and from the Martin and Concetta Greenberg Pancreatic Cancer Institute at FCCC and Pennsylvania DOH Health Research Formula Funds (to K.S.C.).lt;/pgt;