Cancers, Vol. 11, Pages 1881: ROCK2 Confers Acquired Gemcitabine Resistance in Pancreatic Cancer Cells by Upregulating Transcription Factor ZEB1

Cancers, Vol. 11, Pages 1881: ROCK2 Confers Acquired Gemcitabine Resistance in Pancreatic Cancer Cells by Upregulating Transcription Factor ZEB1 Cancers doi: 10.3390/cancers11121881 Authors: Yang Zhou Yunjiang Zhou Keke Wang Tao Li Minda Zhang Yunjia Yang Rui Wang Rong Hu Resistance to chemotherapy is a major clinical challenge in the treatment of pancreatic ductal adenocarcinoma (PDAC). Here, we provide evidence that Rho associated coiled-coil containing protein kinase 2 (ROCK2) maintains gemcitabine resistance in gemcitabine resistant pancreatic cancer cells (GR cells). Pharmacological inhibition or gene silencing of ROCK2 markedly sensitized GR cells to gemcitabine by suppressing the expression of zinc-finger-enhancer binding protein 1 (ZEB1). Mechanically, ROCK2-induced sp1 phosphorylation at Thr-453 enhanced the ability of sp1 binding to ZEB1 promoter regions in a p38-dependent manner. Moreover, transcriptional activation of ZEB1 facilitated GR cells to repair gemcitabine-mediated DNA damage via ATM/p-CHK1 signaling pathway. Our findings demonstrate the essential role of ROCK2 in EMT-induced gemcitabine resistance in pancreatic cancer cells and provide strong evidence for the clinical application of fasudil, a ROCK2 inhibitor, in gemcitabine-refractory PDAC.
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research

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Michal Yalon1†, Amos Toren1,2†, Dina Jabarin2, Edna Fadida3, Shlomi Constantini3 and Ruty Mehrian-Shai1* 1Pediatric Hemato-Oncology, Edmond and Lilly Safra Children's Hospital and Cancer Research Center, Sheba Medical Center, Ramat Gan, Israel 2The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel 3Department of Pediatric Neurosurgery, Dana Children's Hospital, Tel-Aviv-Sourasky Medical Center, Tel Aviv, Israel Pediatric brain tumors are the most common solid tumor type and the leading cause of cancer-related death in children. The immune system plays an important r...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Joe Abdo1, Christopher S. Wichman2, Nicholas E. Dietz1,3, Pawel Ciborowski4, John Fleegel1, Sumeet K. Mittal1,5 and Devendra K. Agrawal1* 1Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE, United States 2Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE, United States 3Department of Pathology, CHI Health Creighton University Medical Center, College of Medicine, Omaha, NE, United States 4Department of Pharmacology, University of Nebraska Medical Center, Omaha, NE, United States 5Norton Thoracic Institute, St....
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
In conclusion, this study demonstrates that WG-391D exhibits strong antitumor activity against ovarian cancer and indicates that the down-regulation of CDC25B by inhibitors could provide a rationale for ovarian cancer therapy. Introduction Ovarian cancer is one of the most common malignances in females. The American Cancer Society estimated that there were 22,240 cases of ovarian cancer, and 14,070 deaths, in the United States in 2018 (1). During its early stages, ovarian cancer can be asymptomatic; hence, ~70% of patients have advanced disease when diagnosed and ultimately develop chemotherapeutic drug resistance an...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Authors: Diab M, Azmi A, Mohammad R, Philip PA Abstract INTRODUCTION: Despite many efforts to improve the outcome of pancreatic ductal adenocarcinoma (PDAC), its prognosis remains poor, which is mostly related to late diagnosis and drug resistance. Improving systemic therapy is considered the major challenge in improving the outcome of this disease. Areas covered: This review covers novel chemotherapy and targeted agents in the treatment of PDAC, with a focus on advanced stage disease. Expert opinion: Current frontline therapies used in the treatment of patients with PDAC with favorable performance status are gemci...
Source: Expert Opinion on Pharmacotherapy - Category: Drugs & Pharmacology Tags: Expert Opin Pharmacother Source Type: research
CONCLUSION: In a single institution, retrospective study, we found that the presence of DDR gene mutations are associated with improved OS in PDAC patients treated with FOLFIRINOX. PMID: 30131383 [PubMed - as supplied by publisher]
Source: Clinical Cancer Research - Category: Cancer & Oncology Authors: Tags: Clin Cancer Res Source Type: research
Objectives Molecular alterations in about 1% of Pancreatic Ductal AdenoCarcinoma(PDAC) includes MicroSatellite Instability (MSI) and damage of DNA Mismatch Repair (MMR) system. Immunotherapy (IT) with ICK inhibitors constitutes a source of personalized treatment for MSI cancer patients and support the evaluation of MSI phenotype in PDAC. The aim of this study is to evaluate MSI in metastatic PDAC patients after surgery featuring first line of chemotherapy (CT) in order to evaluate a possible immunotherapy treatment.
Source: Pancreatology - Category: Gastroenterology Authors: Tags: 4. Experimental pancreatitis and cell biology II Source Type: research
Conclusions: Our results suggest that inactivating HRR-related gene mutations are predictive of response to oxaliplatin-based chemotherapy in patients with PDAC. PMID: 29731985 [PubMed]
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research
Conclusion Personal or family history of breast or ovarian cancers is a feasible, cost-effective risk categorization for screening germlineBRCA mutations in Asian PDAC patients as 10% of this population had the pathogenic mutation herein. Future validation from a large, prospective cohort is needed.
Source: Investigational New Drugs - Category: Drugs & Pharmacology Source Type: research
Pancreatic Cancer: "A Riddle Wrapped in a Mystery inside an Enigma". Clin Cancer Res. 2017 Apr 01;23(7):1629-1637 Authors: Borazanci E, Dang CV, Robey RW, Bates SE, Chabot JA, Von Hoff DD Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most difficult-to-treat cancers. With an increasing incidence and inability to make major progress, it represents the very definition of unmet medical need. Progress has been made in understanding the basic biology-systematic genomic sequencing has led to the recognition that PDAC is not typically a heavily mutated tumor, although there are exce...
Source: Clinical Cancer Research - Category: Cancer & Oncology Authors: Tags: Clin Cancer Res Source Type: research
Pancreatic cancer is characterized by the accumulation of a fibro-inflammatory stroma. Accumulation of the stroma is already evident surrounding Pancreatic Intraepithelial Neoplasias (PanINs), common precursor lesions to pancreatic cancer (Hezel et al., 2006). The stroma is abundantly infiltrated by immune cells, and myeloid cells are a predominant population (Clark et al., 2007). Different myeloid subsets have been correlated with tumor promotion and unmasking of anti-tumor immunity (Liou et al., 2015; Long et al., 2016; Mitchem et al., 2013; Stromnes et al., 2014). Both PanINs and pancreatic cancer and commonly associate...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Immune Drug Development Source Type: research
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