Oncology Commons^™

Beta-Catenin Cleavage Enhances Transcriptional Activation, Tatiana Goretsky, Emily M. Bradford, Qing Ye, Olivia F. Lamping, Tomas Vanagunas, Mary Pat Moyer, Patrick C. Keller, Preetika Sinh, Josep M. Llovet, Tianyan Gao, Qing-Bai She, Linheng Li, Terrence A. Barrett

Internal Medicine Faculty Publications

Nuclear activation of Wnt/β-catenin signaling is required for cell proliferation in inflammation and cancer. Studies from our group indicate that β-catenin activation in colitis and colorectal cancer (CRC) correlates with increased nuclear levels of β-catenin phosphorylated at serine 552 (pβ-Cat⁵⁵²). Biochemical analysis of nuclear extracts from cancer biopsies revealed the existence of low molecular weight (LMW) pβ-Cat⁵⁵², increased to the exclusion of full size (FS) forms of β-catenin. LMW β-catenin lacks both termini, leaving residues in the armadillo repeat intact. Further experiments showed that TCF4 predominantly binds LMW pβ-Cat⁵⁵² in the nucleus of inflamed and …

Tumor Suppressor Pdcd4 Attenuates Sin1 Translation To Inhibit Invasion In Colon Carcinoma, Qing Wang, Jiang Zhu, Ya-Wen Wang, Yong Dai, Yanlei Wang, Chi Wang, Jinpeng Liu, Alyson Baker, Nancy H. Colburn, Hsin-Sheng Yang

Toxicology and Cancer Biology Faculty Publications

Programmed cell death 4 (Pdcd4), a tumor invasion suppressor, is frequently downregulated in colorectal cancer and other cancers. In this study, we find that loss of Pdcd4 increases the activity of mammalian target of rapamycin complex 2 (mTORC2) and thereby upregulates Snail expression. Examining the components of mTORC2 showed that Pdcd4 knockdown increased the protein but not mRNA level of stress-activated-protein kinase interacting protein 1 (Sin1), which resulted from enhanced Sin1 translation. To understand how Pdcd4 regulates Sin1 translation, the SIN1 5′ untranslated region (5′UTR) was fused with luciferase reporter and named as 5′Sin1-Luc. Pdcd4 knockdown/knockout significantly increased the translation …

Probing The Metabolic Phenotype Of Breast Cancer Cells By Multiple Tracer Stable Isotope Resolved Metabolomics, Andrew N. Lane, Julie Tan, Yali Wang, Jun Yan, Richard M. Higashi, Teresa W. -M. Fan

Center for Environmental and Systems Biochemistry Faculty Publications

Breast cancers vary by their origin and specific set of genetic lesions, which gives rise to distinct phenotypes and differential response to targeted and untargeted chemotherapies. To explore the functional differences of different breast cell types, we performed Stable Isotope Resolved Metabolomics (SIRM) studies of one primary breast (HMEC) and three breast cancer cells (MCF-7, MDAMB-231, and ZR75-1) having distinct genotypes and growth characteristics, using ¹³C₆-glucose, ¹³C-1+2-glucose, ¹³C₅,¹⁵N₂-Gln, ¹³C₃-glycerol, and ¹³C₈-octanoate as tracers. These tracers were designed to probe the central energy producing …

Abl Kinase Regulation By Braf/Erk And Cooperation With Akt In Melanoma, Aditi Jain, Rakshamani Tripathi, Courtney P. Turpin, Chi Wang, Rina Plattner

Pharmacology and Nutritional Sciences Faculty Publications

The melanoma incidence continues to increase, and the disease remains incurable for many due to its metastatic nature and high rate of therapeutic resistance. In particular, melanomas harboring BRAF^V600E and PTEN mutations often are resistant to current therapies, including BRAF inhibitors (BRAFi) and immune checkpoint inhibitors. Abl kinases (Abl/Arg) are activated in melanomas and drive progression; however, their mechanism of activation has not been established. Here we elucidate a novel link between BRAF^V600E/ERK signaling and Abl kinases. We demonstrate that BRAF^V600E/ERK play a critical role in binding, phosphorylating and regulating Abl localization and Abl/Arg activation …

Relb Expression Determines The Differential Effects Of Ascorbic Acid In Normal And Cancer Cells, Xiaowei Wei, Yong Xu, Fang Fang Xu, Luksana Chaiswing, David M. Schnell, Teresa Noel, Chi Wang, Jinfei Chen, Daret K. St. Clair, William H. St. Clair

Toxicology and Cancer Biology Faculty Publications

Cancer cells typically experience higher oxidative stress than normal cells, such that elevating pro-oxidant levels can trigger cancer cell death. Although pre-exposure to mild oxidative agents will sensitize cancer cells to radiation, this pre-exposure may also activate the adaptive stress defense system in normal cells. Ascorbic acid is a prototype redox modulator that when infused intravenously appears to kill cancers without injury to normal tissues; however, the mechanisms involved remain elusive. In this study, we show how ascorbic acid kills cancer cells and sensitizes prostate cancer to radiation therapy while also conferring protection upon normal prostate epithelial cells against radiation-induced …

Chronic Ethanol Exposure Enhances The Aggressiveness Of Breast Cancer: The Role Of P38Γ, Mei Xu, Siying Wang, Zhenhua Ren, Jacqueline A. Frank, Xiuwei H. Yang, Zhuo Zhang, Zun-Ji Ke, Xianglin Shi, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Both epidemiological and experimental studies suggest that ethanol may enhance aggressiveness of breast cancer. We have previously demonstrated that short term exposure to ethanol (12–48 hours) increased migration/invasion in breast cancer cells overexpressing ErbB2, but not in breast cancer cells with low expression of ErbB2, such as MCF7, BT20 and T47D breast cancer cells. In this study, we showed that chronic ethanol exposure transformed breast cancer cells that were not responsive to short term ethanol treatment to a more aggressive phenotype. Chronic ethanol exposure (10 days - 2 months) at 100 (22 mM) or 200 mg/dl (44 mM) caused the …

Inflammatory Cytokine Gene Expression In Mesenteric Adipose Tissue During Acute Experimental Colitis, William Conan Mustain, Marlene E. Starr, Joseph Daniel Valentino, Donald A. Cohen, Daiki Okamura, Chi Wang, B. Mark Evers, Hiroshi Saito

Markey Cancer Center Faculty Publications

BACKGROUND: Production of inflammatory cytokines by mesenteric adipose tissue (MAT) has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Animal models of colitis have demonstrated inflammatory changes within MAT, but it is unclear if these changes occur in isolation or as part of a systemic adipose tissue response. It is also unknown what cell types are responsible for cytokine production within MAT. The present study was designed to determine whether cytokine production by MAT during experimental colitis is depot-specific, and also to identify the source of cytokine production within MAT.

METHODS: Experimental colitis was induced in 6-month-old C57BL/6 …