- Browse by Subject
Browsing by Subject "APC"
Now showing 1 - 5 of 5
Results Per Page
Sort Options
Item BID mediates selective killing of APC-deficient cells in intestinal tumor suppression by nonsteroidal antiinflammatory drugs(PNAS, 2014-11-18) Leibowitz, Brian; Qiu, Wei; Buchanan, Monica E.; Zou, Fangdong; Vernon, Philip; Moyer, Mary P.; Yin, Xiao-Ming; Schoen, Robert E.; Yu, Jian; Zhang, Lin; Department of Pathology and Laboratory Medicine, IU School of MedicineColorectal tumorigenesis is driven by genetic alterations in the adenomatous polyposis coli (APC) tumor suppressor pathway and effectively inhibited by nonsteroidal antiinflammatory drugs (NSAIDs). However, how NSAIDs prevent colorectal tumorigenesis has remained obscure. We found that the extrinsic apoptotic pathway and the BH3 interacting-domain death agonist (BID) are activated in adenomas from NSAID-treated patients. Loss of BID abolishes NSAID-mediated tumor suppression, survival benefit, and apoptosis in tumor-initiating stem cells in APC(Min/+) mice. BID-mediated cross-talk between the extrinsic and intrinsic apoptotic pathways is responsible for selective killing of neoplastic cells by NSAIDs. We further demonstrate that NSAIDs induce death receptor signaling in both cancer and normal cells, but only activate BID in cells with APC deficiency and ensuing c-Myc activation. Our results suggest that NSAIDs suppress intestinal tumorigenesis through BID-mediated synthetic lethality triggered by death receptor signaling and gatekeeper mutations, and provide a rationale for developing more effective cancer prevention strategies and agents.Item Chromatin-associated APC regulates gene expression in collaboration with canonical WNT signaling and AP-1(Impact Journals, 2018-07-27) Hankey, William; Chen, Zhong; Bergman, Maxwell J.; Fernandez, Max O.; Hancioglu, Baris; Lan, Xun; Jegga, Anil G.; Zhang, Jie; Jin, Victor X.; Aronow, Bruce J.; Wang, Qianben; Groden, Joanna; Medical and Molecular Genetics, School of MedicineMutation of the APC gene occurs in a high percentage of colorectal tumors and is a central event driving tumor initiation in the large intestine. The APC protein performs multiple tumor suppressor functions including negative regulation of the canonical WNT signaling pathway by both cytoplasmic and nuclear mechanisms. Published reports that APC interacts with β-catenin in the chromatin fraction to repress WNT-activated targets have raised the possibility that chromatin-associated APC participates more broadly in mechanisms of transcriptional control. This screening study has used chromatin immunoprecipitation and next-generation sequencing to identify APC-associated genomic regions in colon cancer cell lines. Initial target selection was performed by comparison and statistical analysis of 3,985 genomic regions associated with the APC protein to whole transcriptome sequencing data from APC-deficient and APC-wild-type colon cancer cells, and two types of murine colon adenomas characterized by activated Wnt signaling. 289 transcripts altered in expression following APC loss in human cells were linked to APC-associated genomic regions. High-confidence targets additionally validated in mouse adenomas included 16 increased and 9 decreased in expression following APC loss, indicating that chromatin-associated APC may antagonize canonical WNT signaling at both WNT-activated and WNT-repressed targets. Motif analysis and comparison to ChIP-seq datasets for other transcription factors identified a prevalence of binding sites for the TCF7L2 and AP-1 transcription factors in APC-associated genomic regions. Our results indicate that canonical WNT signaling can collaborate with or antagonize the AP-1 transcription factor to fine-tune the expression of shared target genes in the colorectal epithelium. Future therapeutic strategies for APC-deficient colorectal cancers might be expanded to include agents targeting the AP-1 pathway.Item Effect of Adenomatous Polyposis Coli Loss on Tumorigenic Potential in Pancreatic Ductal Adenocarcinoma(MDPI, 2019-09-14) Cole, Jennifer M.; Simmons, Kaitlyn; Prosperi, Jenifer R.; Biochemistry and Molecular Biology, School of MedicineLoss of the Adenomatous Polyposis Coli (APC) tumor suppressor in colorectal cancer elicits rapid signaling through the Wnt/β-catenin signaling pathway. In contrast to this well-established role of APC, recent studies from our laboratory demonstrated that APC functions through Wnt-independent pathways to mediate in vitro and in vivo models of breast tumorigenesis. Pancreatic ductal adenocarcinoma (PDAC) has an overall median survival of less than one year with a 5-year survival rate of 7.2%. APC is lost in a subset of pancreatic cancers, but the impact on Wnt signaling or tumor development is unclear. Given the lack of effective treatment strategies for pancreatic cancer, it is important to understand the functional implications of APC loss in pancreatic cancer cell lines. Therefore, the goal of this project is to study how APC loss affects Wnt pathway activation and in vitro tumor phenotypes. Using lentiviral shRNA, we successfully knocked down APC expression in six pancreatic cancer cell lines (AsPC-1, BxPC3, L3.6pl, HPAF-II, Hs 766T, MIA PaCa-2). No changes were observed in localization of β-catenin or reporter assays to assess β-catenin/TCF interaction. Despite this lack of Wnt/β-catenin pathway activation, the majority of APC knockdown cell lines exhibit an increase in cell proliferation. Cell migration assays showed that the BxPC-3 and L3.6pl cells were impacted by APC knockdown, showing faster wound healing in scratch wound assays. Interestingly, APC knockdown had no effect on gemcitabine treatment, which is the standard care for pancreatic cancer. It is important to understand the functional implications of APC loss in pancreatic cancer cells lines, which could be used as a target for therapeutics.Item SOD1G93A transgenic mouse CD4+ T cells mediate neuroprotection after facial nerve axotomy when removed from a suppressive peripheral microenvironment(Elsevier B.V., 2014-08) Mesnard-Hoaglin, Nichole A.; Xin, Junping; Haulcomb, Melissa M.; Batka, Richard J.; Sanders, Virginia M.; Jones, Kathryn J.; Department of Anatomy & Cell Biology, IU School of MedicineAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving motoneuron (MN) axonal withdrawal and cell death. Previously, we established that facial MN (FMN) survival levels in the SOD1G93A transgenic mouse model of ALS are reduced and nerve regeneration is delayed, similar to immunodeficient RAG2-/- mice, after facial nerve axotomy. The objective of this study was to examine the functionality of SOD1G93A splenic microenvironment, focusing on CD4+ T cells, with regard to defects in immune-mediated neuroprotection of injured MN. We utilized the RAG2-/- and SOD1G93A mouse models, along with the facial nerve axotomy paradigm and a variety of cellular adoptive transfers, to assess immune-mediated neuroprotection of FMN survival levels. We determined that adoptively transferred SOD1G93A unfractionated splenocytes into RAG2-/- mice were unable to support FMN survival after axotomy, but that adoptive transfer of isolated SOD1G93A CD4+ T cells could. Although WT unfractionated splenocytes adoptively transferred into SOD1G93A mice were able to maintain FMN survival levels, WT CD4+ T cells alone could not. Importantly, these results suggest that SOD1G93A CD4+ T cells retain neuroprotective functionality when removed from a dysfunctional SOD1G93A peripheral splenic microenvironment. These results also indicate that the SOD1G93A central nervous system microenvironment is able to re-activate CD4+ T cells for immune-mediated neuroprotection when a permissive peripheral microenvironment exists. We hypothesize that dysfunctional SOD1G93A peripheral splenic microenvironment may compromise neuroprotective CD4+ T cell activation and/or differentiation, which, in turn, results in impaired immune-mediated neuroprotection for MN survival after peripheral axotomy in SOD1G93A mice.Item The Symptom Experience of Patients With Advanced Pancreatic Cancer: An Integrative Review(Lippincott, Williams, and Wilkins, 2017-01) Tang, Chia-Chun; Von Ah, Diane; Fulton, Janet S.; School of NursingBackground: Pancreatic cancer is a devastating disease with limited treatment options. More than 80% of pancreatic cancers are diagnosed in advanced stages and often have debilitating symptoms, making symptom management paramount, yet the symptom experience of patients with advanced pancreatic cancer (APC) is not well understood. Objective: The purpose of this integrative review is to synthesize the current evidence regarding the symptom experience of patients with APC. Method: An integrative literature review was conducted to identify the patient symptom experience in studies published from 2005 to 2015. Results: Sixteen studies met the inclusion criteria. All studies used a quantitative approach; 44% were quasi-experimental, 31% were descriptive, and 25% were correlational. Physical symptoms, especially pain, were the primary focus in most studies. Fatigue, loss of appetite, and impaired sense of well-being were prevalent and reported by patients to be of high intensity. Few studies examined psychological symptoms in patients with APC, although anxiety and depression were noted. Conclusion: Findings suggest that physical and psychological symptoms are prevalent, some with high intensity. Preselection of symptom inventories limits our ability to fully understand the symptom experience of patients with APC. Future qualitative work is needed to provide a more in-depth understanding of symptoms, especially symptom quality and distress level, from patients' perspectives. More studies are needed to explore psychological symptoms and the interaction of physical and psychological symptoms. Implications for Practice: Findings help healthcare givers to better understand the symptom experience of their APC patients.