Browsing by Subject "drug resistance"

Now showing 1 - 6 of 6
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    Bioinspired One Cell Culture Isolates Highly Tumorigenic and Metastatic Cancer Stem Cells Capable of Multilineage Differentiation
    (Wiley, 2020-04-28) Wang, Hai; Agarwal, Pranay; Jiang, Bin; Stewart, Samantha; Liu, Xuanyou; Liang, Yutong; Hancioglu, Baris; Webb, Amy; Fisher, John P.; Liu, Zhenguo; Lu, Xiongbin; Tkaczuk, Katherine H. R.; He, Xiaoming; Medical and Molecular Genetics, School of Medicine
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    Determinants of 14-3-3σ dimerization and function in drug and radiation resistance
    (2013-11) Li, Zhaomin; Peng, Hui; Qin, Li; Qi, Jing; Zuo, Xiaobing; Liu, Jing-Yuan; Zhang, Jian-Ting; Department of Pharmacology and Toxicology, IU School of Medicine
    Many proteins exist and function as homodimers. Understanding the detailed mechanism driving the homodimerization is important and will impact future studies targeting the “undruggable” oncogenic protein dimers. In this study, we used 14-3-3σ as a model homodimeric protein and performed a systematic investigation of the potential roles of amino acid residues in the interface for homodimerization. Unlike other members of the conserved 14-3-3 protein family, 14-3-3σ prefers to form a homodimer with two subareas in the dimeric interface that has 180° symmetry. We found that both subareas of the dimeric interface are required to maintain full dimerization activity. Although the interfacial hydrophobic core residues Leu12 and Tyr84 play important roles in 14-3-3σ dimerization, the non-core residue Phe25 appears to be more important in controlling 14-3-3σ dimerization activity. Interestingly, a similar non-core residue (Val81) is less important than Phe25 in contributing to 14-3-3σ dimerization. Furthermore, dissociating dimeric 14-3-3σ into monomers by mutating the Leu12, Phe25, or Tyr84 dimerization residue individually diminished the function of 14-3-3σ in resisting drug-induced apoptosis and in arresting cells at G2/M phase in response to DNA-damaging treatment. Thus, dimerization appears to be required for the function of 14-3-3σ.
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    Functional significance of Hippo/YAP signaling for drug resistance in colorectal cancer
    (Wiley, 2018) Song, Ruolan; Gu, Dongsheng; Zhang, Lining; Zhang, Xiaoli; Yu, Beiqin; Liu, Bingya; Xie, Jingwu; Pediatrics, School of Medicine
    Colorectal cancer is a leading cause of cancer‐related death worldwide. While early stage colorectal cancer can be removed by surgery, patients with advanced disease are treated by chemotherapy, with 5‐Fluorouracil (5‐FU) as a main ingredient. However, most patients with advanced colorectal cancer eventually succumb to the disease despite some responded initially. Thus, identifying molecular mechanisms responsible for drug resistance will help design novel strategies to treat colorectal cancer. In this study, we analyzed an acquired 5‐FU resistant cell line, LoVo‐R, and determined that elevated expression of YAP target genes is a major alteration in the 5‐FU resistant cells. Hippo/YAP signaling, a pathway essential for cell polarity, is an important regulator for tissue homeostasis, organ size, and stem cells. We demonstrated that knockdown of YAP1 sensitized LoVo‐R cells to 5‐FU treatment in cultured cells and in mice. The relevance of our studies to colorectal cancer patients is reflected by our discovery that high expression of YAP target genes in the tumor was associated with an increased risk of cancer relapse and poor survival in a larger cohort of colorectal cancer patients who underwent 5‐FU‐related chemotherapy. Taken together, we demonstrate a critical role of YAP signaling for drug resistance in colorectal cancer.
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    Lack of EGF receptor contributes to drug sensitivity of human germline cells
    (2005-01) Park, S.J.; Armstrong, S.; Kim, C.H.; Yu, M.; Robertson, K.; Kelley, Mark R.; Lee, S.H.
    Germline mutations have been associated with generation of various types of tumour. In this study, we investigated genetic alteration of germline tumours that affect the drug sensitivity of cells. Although all germline tumour cells we tested were hypersensitive to DNA-damaging drugs, no significant alteration was observed in their DNA repair activity or the expression of DNA repair proteins. In contrast, germline tumours expressed very low level of epidermal growth factor receptor (EGFR) compared to drug-resistant ovarian cancer cells. An immunohistochemical analysis indicated that most of the primary germline tumours we tested expressed very low level of EGFR. In accordance with this, overexpression of EGFR in germline tumour cells showed an increase in drug resistance, suggesting that a lack of EGFR, at least in part, contributes to the drug sensitivity of germline tumours.
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    Small molecule inhibition of CBP/catenin interactions eliminates drug resistant clones in acute lymphoblastic leukemia
    (NPG - Nature Publishing Group, 2014-04-24) Gang, Eun Ji; Hsieh, Yao-Te; Pham, Jennifer; Zhao, Yi; Nguyen, Cu; Huantes, Sandra; Park, Eugene; Naing, Khatija; Klemm, Lars; Swaminathan, Srividya; Conway, Edward M.; Pelus, Louis M.; Crispino, John; Mullighan, Charles; McMillan, Michael; Müschen, Markus; Kahn, Michael; Kim, Yong-Mi; Department of Microbiology & Immunology, School of Medicine
    Drug resistance in acute lymphoblastic leukemia (ALL) remains a major problem warranting new treatment strategies. Wnt/catenin signaling is critical for the self-renewal of normal hematopoietic progenitor cells. Deregulated Wnt signaling is evident in chronic and acute myeloid leukemia, however little is known about ALL. Differential interaction of catenin with either the Kat3 coactivator CREBBP (CBP) or the highly homologous EP300 (p300) is critical to determine divergent cellular responses and provides a rationale for the regulation of both proliferation and differentiation by the Wnt signaling pathway. Usage of the coactivator CBP by catenin leads to transcriptional activation of cassettes of genes that are involved in maintenance of progenitor cell self-renewal. However, the use of the coactivator p300, leads to activation of genes involved in the initiation of differentiation. ICG-001 is a novel small molecule modulator of Wnt/catenin signaling, which specifically binds to the N-terminus of CBP and not p300, within amino acids 1–110, thereby disrupting the interaction between CBP and catenin. Here, we report that selective disruption of the CBP/β- and γ-catenin interactions using ICG-001 leads to differentiation of pre-B ALL cells and loss of self-renewal capacity. Survivin, an inhibitor-of-apoptosis protein, was also downregulated in primary ALL after treatment with ICG-001. Using ChIP assay, we demonstrate occupancy by CBP of the survivin promoter, which is decreased by ICG-001 in primary ALL. CBP-mutations have been recently identified in a significant percentage of ALL patients, however, almost all of the identified mutations reported occur C-terminal to the binding site for ICG-001. Importantly, ICG-001, regardless of CBP mutational status and chromosomal aberration, leads to eradication of drug-resistant primary leukemia in combination with conventional therapy in vitro and significantly prolongs the survival of NOD/SCID mice engrafted with primary ALL. Therefore, specifically inhibiting CBP/catenin transcription represents a novel approach to overcome relapse in ALL.
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    Targeting survivin for therapeutic discovery: past, present, and future promises
    (Elsevier, 2017-10) Peery, Robert C.; Liu, Jing-Yuan; Zhang, Jian-Ting; Pharmacology and Toxicology, School of Medicine
    Survivin, the smallest member of the inhibitor of apoptosis protein (IAP) family, is overexpressed in cells of almost all cancers but not in most normal tissues in adults. Survivin expression is required for cancer cell survival and knocking down its expression or inhibiting its function using molecular approaches results in spontaneous apoptosis. Thus, survivin is an attractive and perhaps ideal target for cancer drug discovery. However, a US Food and Drug Administration (FDA)-approved drug targeting survivin has yet to emerge. In this Foundation Review, we examine and evaluate various strategies that have been used to target survivin and the stages of each survivin inhibitor to help understand this lack of success. We also provide future perspectives moving forward in targeting survivin for drug discovery.