Z Gastroenterol 2017; 55(08): e57-e299
DOI: 10.1055/s-0037-1604923
Kurzvorträge
Pankreas
Mechanismen der Pankreaskarzinomentstehung: Donnerstag, 14 September 2017, 08:00 – 09:20, Coventry/Forschungsforum 4
Georg Thieme Verlag KG Stuttgart · New York

VCP/p97 is upregulated in pancreatic cancer and promotes proliferation and cell cycle progression in cancer cells

BP Kaistha
1   Centre for Tumor Biology and Immunology, Clinic for Gastroenterology and Endocrinology, Marburg, Deutschland
,
S Schimanski
1   Centre for Tumor Biology and Immunology, Clinic for Gastroenterology and Endocrinology, Marburg, Deutschland
,
TM Gress
1   Centre for Tumor Biology and Immunology, Clinic for Gastroenterology and Endocrinology, Marburg, Deutschland
,
M Buchholz
1   Centre for Tumor Biology and Immunology, Clinic for Gastroenterology and Endocrinology, Marburg, Deutschland
› Author Affiliations
Further Information

Publication History

Publication Date:
02 August 2017 (online)

 

Introduction:

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors. With a five-year survival rate still below 6% since last few decades, there is a specific need to look for new target genes for therapeutic approaches. Over the years, our group has undertaken various screening approaches to identify new molecular targets for therapeutic interventions and thereby tried to address this lacuna in the pancreatic cancer research.

Material and methods:

shRNA based loss of function screen, siRNAs, pharmacological inhibitor, qRT-PCR, cell proliferation and viability assays, Western blots.

Results:

We undertook barcode labelled short-hairpin (shRNA) library screen in pancreatic cancer cells and looked for genes necessary for the cancer cell survival and progression. The list was refined further for the drugability of the new putative genes selected. Among various genes thus identified a segratase VCP, an AAA- type ATPase also known as p97 and CDC48, came out as a conspicuous gene differentially regulated in primary human cancer tissues. Using pharmacological and siRNA based inhibition/knockdown approaches, we show that expression of VCP is essential for the proliferation and survival of pancreatic cancer cells. These effects seem primarily mediated by attenuation of cell cycle progression as evidenced by upregulation of p21 and down regulation of Cyclin D1, accumulation of DNA damage (phos. H2A.X) and finally leading the cells into apoptosis (PARP cleavage).

Conclusions:

Our in vitro data shows that expression of VCP is crucial for proliferation, viability and cell cycle progression in pancreatic cancer cells. Since VCP is overexpressed in cancer tissues, it can serve as an attractive new target for specific therapeutic interventions in solo or in combination therapies, especially given the fact that a specific inhibitor is already for this molecular target. A clear insight into pathophysiological role(s) of VCP in the onset and progression of pancreatic cancer is expected to emerge with the planned in vivo experiments.