Cancers, Vol. 13, Pages 5076: Phospho-Ser784-VCP Drives Resistance of Pancreatic Ductal Adenocarcinoma to Genotoxic Chemotherapies and Predicts the Chemo-Sensitizing Effect of VCP Inhibitor

Cancers, Vol. 13, Pages 5076: Phospho-Ser784-VCP Drives Resistance of Pancreatic Ductal Adenocarcinoma to Genotoxic Chemotherapies and Predicts the Chemo-Sensitizing Effect of VCP Inhibitor Cancers doi: 10.3390/cancers13205076 Authors: Faliang Wang Kiran Vij Lin Li Paarth Dodhiawala Kian-Huat Lim Jieya Shao Pancreatic ductal adenocarcinoma (PDAC) patients have a dismal prognosis due in large part to chemotherapy resistance. However, a small subset containing defects in the DNA damage response (DDR) pathways are chemotherapy-sensitive. Identifying intrinsic and therapeutically inducible DDR defects can improve precision and efficacy of chemotherapies for PDAC. DNA repair requires dynamic reorganization of chromatin-associated proteins, which is orchestrated by the AAA+ ATPase VCP. We recently discovered that the DDR function of VCP is selectively activated by Ser784 phosphorylation. In this paper, we show that pSer784-VCP but not total VCP levels in primary PDAC tumors negatively correlate with patient survival. In PDAC cell lines, different pSer784-VCP levels are induced by genotoxic chemotherapy agents and positively correlate with genome stability and cell survival. Causal effects of pSer784-VCP on DNA repair and cell survival were confirmed using VCP knockdown and functional rescue. Importantly, DNA damage-induced pSer784-VCP rather than total VCP levels in PDAC cell lines predict their chemotherapy response and chemo-sensitizing ability of selective VCP ...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research

Related Links:

World J Gastroenterol. 2021 Oct 28;27(40):6775-6793. doi: 10.3748/wjg.v27.i40.6775.ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor with high lethality. Even with surgery, radiotherapy, chemotherapy, and other locoregional or systemic therapies, the survival rates for PDAC are low and have not significantly changed in the past decades. The special characteristics of the PDAC's microenvironment and its complex immune escape mechanism need to be considered when designing novel therapeutic approaches in this disease. PDAC is characterized by chronic inflammation with a high rate of tumor-associated macro...
Source: World Journal of Gastroenterology : WJG - Category: Gastroenterology Authors: Source Type: research
World J Gastroenterol. 2021 Oct 21;27(39):6527-6550. doi: 10.3748/wjg.v27.i39.6527.ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United States. Although chemotherapeutic regimens such as gemcitabine+ nab-paclitaxel and FOLFIRINOX (FOLinic acid, 5-Fluroruracil, IRINotecan, and Oxaliplatin) significantly improve patient survival, the prevalence of therapy resistance remains a major roadblock in the success of these agents. This review discusses the molecular mechanisms that play a crucial role in PDAC therapy resistance and how a better understanding of these mecha...
Source: World Journal of Gastroenterology - Category: Gastroenterology Authors: Source Type: research
More News: Adenocarcinoma | Cancer | Cancer & Oncology | Chemotherapy | Gastroschisis Repair | Pancreas | Pancreatic Cancer