scholarly journals USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer

2021 ◽  
Author(s):  
Pingping Hou ◽  
Xingdi Ma ◽  
Zecheng Yang ◽  
Qiang Zhang ◽  
Chang-Jiun Wu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Amino Acid ◽  
Drug Target ◽  
Resistance Mechanism ◽  
Ductal Adenocarcinoma ◽  
Activating Mutations ◽  
Intracellular Amino Acid ◽  
Amino Acid Levels ◽  
Novel Drug ◽  
Tumor Maintenance

Activating mutations in KRAS (KRAS*) are present in nearly all pancreatic ductal adenocarcinoma (PDAC) cases and critical for tumor maintenance. By using an inducible KRAS* PDAC mouse model, we identified a deubiquitinase USP21-driven resistance mechanism to anti-KRAS* therapy. USP21 promotes KRAS*-independent tumor growth via its regulation of MARK3-induced macropinocytosis, which serves to maintain intracellular amino acid levels for anabolic growth. The USP21-mediated KRAS* bypass, coupled with the frequent amplification of USP21 in human PDAC tumors, encourages the assessment of USP21 as a novel drug target as well as a potential parameter that may affect responsiveness to emergent anti-KRAS* therapy.

RAS in pancreatic cancer

2019 ◽  
Vol 47 (4) ◽  
pp. 961-972 ◽  
Author(s):  
Simone Lanfredini ◽  
Asmita Thapa ◽  
Eric O'Neill
Keyword(s):  
Pancreatic Cancer ◽  
Neuroendocrine Tumour ◽  
Critical Role ◽  
Acinar Cell Carcinoma ◽  
Genetically Engineered ◽  
Ductal Adenocarcinoma ◽  
Kras Mutations ◽  
Activating Mutations ◽  
Downstream Effectors ◽  
Almost All

Abstract The pancreas is a gland composed mainly by endocrine and exocrine cells, giving rise to three main tumour types. Pancreatic neuroendocrine tumour or PNET arise from the endocrine portion of the pancreas. On the contrary, pancreatic exocrine neoplasms include pancreatic ductal adenocarcinoma (PDAC) and acinar cell carcinoma. PDAC is the most common type of pancreatic cancer and one of the leading causes of cancer-related death. It has been shown that less than 3% of PDAC patients have an overall survival of up to 5 years in the U.K. This mainly arises since the majority of patients diagnosed with PDAC present with advanced unresectable disease, which is highly resistant to all forms of chemotherapy and radiotherapy. Activating mutations of an isoform of the RAS protein, KRAS, are found in almost all PDAC cases and occur during early stages of malignant transformation. KRAS mutations play a critical role as they are involved in both initiating and maintaining PDAC development. The interaction of RAS with GDP/GTP along with its recruitment to the membrane affects transduction of its activating signals to downstream effectors. In this review, we aim to summarise different mutations of RAS and their prevalence in pancreatic cancer along with other RAS-induced tumours. In addition, we briefly discuss the genetically engineered mouse models that have been developed to study KRAS-mutated adenocarcinomas in the pancreas. These provide an opportunity to also address the importance of targeting RAS for better treatment response in PDAC patients along with the challenges incurred herein.

scholarly journals Tumor cross-talk networks promote growth and support immune evasion in pancreatic cancer

2018 ◽  
Vol 315 (1) ◽  
pp. G27-G35 ◽  
Author(s):  
Christopher J. Halbrook ◽  
Marina Pasca di Magliano ◽  
Costas A. Lyssiotis
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Immune Evasion ◽  
Cross Talk ◽  
Tissue Repair ◽  
Ductal Adenocarcinoma ◽  
Normal Tissues ◽  
Pancreatic Cancer Cells ◽  
Key Driver ◽  
Tumor Maintenance

In the event of an injury, normal tissues exit quiescent homeostasis and rapidly engage a complex stromal and immune program. These tissue repair responses are hijacked and become dysregulated in carcinogenesis to form a growth-supportive tumor microenvironment. In pancreatic ductal adenocarcinoma (PDA), which remains one of the deadliest major cancers, the microenvironment is a key driver of tumor maintenance that impedes many avenues of therapy. In this review, we outline recent efforts made to uncover the microenvironmental cross-talk mechanisms that support pancreatic cancer cells, and we detail the strategies that have been undertaken to help overcome these barriers.

scholarly journals Amino acid transporter SLC6A14 is a novel and effective drug target for pancreatic cancer

2016 ◽  
Vol 173 (23) ◽  
pp. 3292-3306 ◽  
Author(s):  
V Coothankandaswamy ◽  
S Cao ◽  
Y Xu ◽  
P D Prasad ◽  
P K Singh ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Amino Acid ◽  
Drug Target ◽  
Amino Acid Transporter ◽  
Effective Drug ◽  
Acid Transporter

Cell density affects prolidase and prolinase activity and intracellular amino acid levels in cultured human cells

1985 ◽  
Vol 150 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Isaac Myara ◽  
Christiane Charpentier ◽  
Marthe Gautier ◽  
Alain Lemonnier
Keyword(s):  
Amino Acid ◽  
Cell Density ◽  
Human Cells ◽  
Intracellular Amino Acid ◽  
Cultured Human Cells ◽  
Amino Acid Levels

scholarly journals The E3 ubiquitin ligase ZNRF2 is a substrate of mTORC1 and regulates its activation by amino acids

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Gerta Hoxhaj ◽  
Edward Caddye ◽  
Ayaz Najafov ◽  
Vanessa P Houde ◽  
Catherine Johnson ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Ubiquitin Ligase ◽  
Protein Phosphatase ◽  
E3 Ubiquitin Ligase ◽  
Mechanistic Target Of Rapamycin ◽  
Rag Gtpases ◽  
Intracellular Amino Acid ◽  
Amino Acid Levels ◽  
Amino Acid Sensing

The mechanistic Target of Rapamycin complex 1 (mTORC1) senses intracellular amino acid levels through an intricate machinery, which includes the Rag GTPases, Ragulator and vacuolar ATPase (V-ATPase). The membrane-associated E3 ubiquitin ligase ZNRF2 is released into the cytosol upon its phosphorylation by Akt. In this study, we show that ZNRF2 interacts with mTOR on membranes, promoting the amino acid-stimulated translocation of mTORC1 to lysosomes and its activation in human cells. ZNRF2 also interacts with the V-ATPase and preserves lysosomal acidity. Moreover, knockdown of ZNRF2 decreases cell size and cell proliferation. Upon growth factor and amino acid stimulation, mTORC1 phosphorylates ZNRF2 on Ser145, and this phosphosite is dephosphorylated by protein phosphatase 6. Ser145 phosphorylation stimulates vesicle-to-cytosol translocation of ZNRF2 and forms a novel negative feedback on mTORC1. Our findings uncover ZNRF2 as a component of the amino acid sensing machinery that acts upstream of Rag-GTPases and the V-ATPase to activate mTORC1.

scholarly journals GABAB receptor is a novel drug target for pancreatic cancer

Cancer ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 767-778 ◽  
Author(s):  
Hildegard M. Schuller ◽  
Hussein A. N. Al-Wadei ◽  
Mourad Majidi
Keyword(s):  
Pancreatic Cancer ◽  
Drug Target ◽  
Gabab Receptor ◽  
Novel Drug
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