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bioRxiv · 10.1101/2024.08.21.609015

Cyclin C Promotes Pancreatic Development and Suppresses Cancer Initiation Through Maintenance of the Autophagy-Lysosome Pathway

Hanley, S. E.·Cai, K. Q.·Willis, S. D.·Stieg, D. C.·Klein Szanto, A. J.·Campbell, K. S.·Strich, R.
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Abstract

The cyclin C (Ccnc)-Cdk8/Cdk19 kinases are components of the Mediator that represses or activates gene transcription. The present study found that Ccnc is required for both steady state and induced autophagic gene transcription in mouse embryonic fibroblasts. In vivo, pancreatic ablation of Ccnc (CcncPan{Delta}) resulted in phenotypes (islet atrophy, acinar cell damage) also observed in autophagy deficient models. However, CcncPan{Delta}animals displayed more dramatic phenotypes including earlier death and accelerated acinar ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) precancerous lesion formation when these animals also expressed oncogenic KrasG12D. Consistent with the in vivo results, a KrasG12D; CcncPan{Delta} pancreatic derived cell line displayed reduced autophagy lysosome pathway (ALP) activation. Although autophagy deficient acinar cells undergo Tp53-dependent cell death, histopathology revealed that KrasG12D;Ccnc-/- (PC) pancreata did not allowing damaged cells to keep dividing. Therefore, Ccnc both supports normal ALP function protecting endocrine and exocrine cell but also kills damaged cells before they become malignant. Finally, the PC cell line displayed reduced proteasome function rendering cells hypersensitive to proteasome inhibitors. This hypersensitivity was also observed in disparate Ccnc-/- tumor cell lines or in Ccnc+/+ tumor cells co-treated with Cdk8/Cdk19 inhibitors. These findings suggest a new avenue to target pancreatic neoplasms by inhibiting cyclin C-Cdk8/Cdk19 proteasome activity.

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Hanley, S. E., Cai, K. Q., Willis, S. D., Stieg, D. C., Klein Szanto, A. J., Campbell, K. S., Strich, R.. 2024-08-22. Cyclin C Promotes Pancreatic Development and Suppresses Cancer Initiation Through Maintenance of the Autophagy-Lysosome Pathway. https://doi.org/10.1101/2024.08.21.609015

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