Dataset Information

LIMS1 Promotes Pancreatic Cancer Cell Survival under Oxygen-Glucose Deprivation Conditions by Enhancing HIF1A Protein Translation.

ABSTRACT: PURPOSE:Oxygen and glucose deprivation is a common feature of the solid tumor. Regulatory network underlying the adaptation of cancer cells to the harsh microenvironment remains unclear. We determined the mechanistic role of LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1) in cancer cell survival under oxygen-glucose deprivation conditions. EXPERIMENTAL DESIGN:The expression level of LIMS1 was determined by IHC staining and analyzing the mRNA expression profiles from The Cancer Genome Atlas of three human solid tumors. Roles of LIMS1 in cancer cell metabolism and growth were determined by molecular and cell biology methods. A jetPEI nanocarrier was used as the vehicle for anti-LIMS1 siRNAs in mouse models of cancer therapeutics. RESULTS:LIMS1 expression was drastically elevated in pancreatic ductal adenocarcinoma (PDAC). High LIMS1 level was associated with advanced TNM stage and poor prognosis of patients with tumor. Increased LIMS1 expression was pivotal for tumor cells to survive in the oxygen-glucose deprivation conditions. Mechanistically, LIMS1 enhanced GLUT1 expression and membrane translocation, which facilitated tumor cell adaptation to the glucose deprivation stress. Furthermore, LIMS1 promoted HIF1A protein translation by activating AKT/mTOR signaling, while hypoxia-inducible factor 1 (HIF1) transactivated LIMS1 transcription, thus forming a positive feedback loop in PDAC cell adaptation to oxygen deprivation stress. Inhibition of LIMS1 with jetPEI nanocarrier-delivered anti-LIMS1 siRNAs significantly increased cell death and suppressed tumor growth. CONCLUSIONS:LIMS1 promotes pancreatic cancer cell survival under oxygen-glucose deprivation conditions by activating AKT/mTOR signaling and enhancing HIF1A protein translation. LIMS1 is crucial for tumor adaptation to oxygen-glucose deprivation conditions and is a promising therapeutic target for cancer treatment.

SUBMITTER: Huang C

PROVIDER: S-EPMC6759834 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:We previously reported that Corynebacterium glutamicum strain ?ldhA?ppc+alaD+gapA, overexpressing glyceraldehyde-3-phosphate dehydrogenase-encoding gapA, shows significantly improved glucose consumption and alanine formation under oxygen deprivation conditions (T. Jojima, M. Fujii, E. Mori, M. Inui, and H. Yukawa, Appl. Microbiol. Biotechnol. 87:159-165, 2010). In this study, we employ stepwise overexpression and chromosomal integration of a total of four genes encoding glycolytic enzymes (herein referred to as glycolytic genes) to demonstrate further successive improvements in C. glutamicum glucose metabolism under oxygen deprivation. In addition to gapA, overexpressing pyruvate kinase-encoding pyk and phosphofructokinase-encoding pfk enabled strain GLY2/pCRD500 to realize respective 13% and 20% improved rates of glucose consumption and alanine formation compared to GLY1/pCRD500. Subsequent overexpression of glucose-6-phosphate isomerase-encoding gpi in strain GLY3/pCRD500 further improved its glucose metabolism. Notably, both alanine productivity and yield increased after each overexpression step. After 48 h of incubation, GLY3/pCRD500 produced 2,430 mM alanine at a yield of 91.8%. This was 6.4-fold higher productivity than that of the wild-type strain. Intracellular metabolite analysis showed that gapA overexpression led to a decreased concentration of metabolites upstream of glyceraldehyde-3-phosphate dehydrogenase, suggesting that the overexpression resolved a bottleneck in glycolysis. Changing ratios of the extracellular metabolites by overexpression of glycolytic genes resulted in reduction of the intracellular NADH/NAD(+) ratio, which also plays an important role on the improvement of glucose consumption. Enhanced alanine dehydrogenase activity using a high-copy-number plasmid further accelerated the overall alanine productivity. Increase in glycolytic enzyme activities is a promising approach to make drastic progress in growth-arrested bioprocesses.

Dataset Information

LIMS1 Promotes Pancreatic Cancer Cell Survival under Oxygen-Glucose Deprivation Conditions by Enhancing HIF1A Protein Translation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets