Abstract
Primary cilia are hair-like projections that protrude from most mammalian cells and mediate various extracellular signaling pathways. Pancreatic ductal adenocarcinoma (PDAC) cells are known to lose their primary cilia, but the relevance of this phenomenon remains unclear. In this study, we generated PDAC-originated Panc1 cells devoid of primary cilia by mutating a centriolar protein, centrosomal protein 164 (CEP164), which is required for ciliogenesis. CEP164 depletion enhanced the clonogenicity of Panc1 cells, along with chemically induced elimination of primary cilia, suggesting that a lack of these organelles promotes PDAC cells proliferation. In addition, the loss of CEP164 altered the cell cycle progression irrespective of absence of primary cilia. We found that CEP164 was co-localized with the GLI2 transcription factor at the mother centriole and controlled its activation, thus inducing Cyclin D-CDK6 expression. Furthermore, CEP164-mutated Panc1 cells were significantly tolerant to KRAS depletion-dependent growth inhibition. This study suggests that CEP164 deficiency is advantageous for PDAC cells proliferation due to not only lack of ciliation but also cilia-independent GLI2-Cyclin D/CDK6 activation, and that CEP164 is a potential therapeutic target for PDAC.
Highlights
Most human cells express a hair-like projection on their surface, referred to as primary cilium (Ishikawa and Marshall, 2011)
Ectopic centrosomal protein 164 (CEP164) expression significantly reversed this phenotype in Cep164-1 cells (Supplementary Figure 4). These results suggest that the inhibitory effect of Kirsten rat sarcoma viral oncogene homolog (KRAS) ablation on the proliferation of Pancreatic ductal adenocarcinoma (PDAC) cells partly depends on CEP164 expression
We targeted CEP164 to obtain de-ciliated Panc1 cells since this protein is known to be required for ciliogenesis in mammalian cells (Graser et al, 2007; Schmidt et al, 2012; Daly et al, 2016; Siller et al, 2017)
Summary
Most human cells express a hair-like projection on their surface, referred to as primary cilium (Ishikawa and Marshall, 2011). As this organelle houses multiple signaling molecules that receive extracellular stimuli and transduce them into the cell body, it is considered to be the cells’ sensor. The primary cilium extends from the centrioles, a pair of cylinder-like structures in the centrosome which plays a pivotal role in mitotic spindle formation (Kobayashi and Dynlacht, 2011). Serum deprivation of cultured mammalian cells triggers primary cilium assembly; small vesicles initially attach onto the DA, an enlarged vesicle (the ciliary vesicle) covers the top of the mother centriole, developing into the ciliary membrane and encapsulating the Overgrowth of CEP164-Mutated PDAC Cells ciliary shaft (Wang and Dynlacht, 2018). Several studies have reported that the ablation of DA proteins including centrosomal protein 164 (CEP164) causes severe loss of primary cilia (designated as “de-ciliation”) in cultured mammalian cells (Graser et al, 2007; Schmidt et al, 2012; Tanos et al, 2013)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
