The regulation of constitutive NF-κB activity by glycogen synthase kinase-3 in pancreatic cancer

The development of pancreatic cancer chemotherapy has evolved into targeting the complex signaling pathways associated with disease progression. Recent focus has been made on targeting the constitutive activation of the transcription factor, NF-κB. However, advancement of this therapeutic strategy is dependent on fully understanding the elusive mechanisms underlying constitutive NF-κB activity in pancreatic cancer. Glycogen synthase kinase-3 has previously been implicated in regulating pro-survival NF-κB signaling in pancreatic cancer cells through an unknown mechanism. Moreover, TGF-β activated kinase 1 (TAK1) is a known regulator of NF-κB activity in human cancers, but its role in pancreatic cancer has yet to be established. In this report, we characterize GSK-3-dependent NF-κB regulation in pancreatic cancer cells and provide initial evidence that GSK-3 facilitates constitutive IκB kinase (IKK) activity. Our data also indicates that TAK1 is active in pancreatic cancer and contributes to constitutive NF-κB activation. Importantly, GSK-3 may be functionally linked to IKK through the phosphorylation of TAK1 at serine 412. Collectively, we propose that constitutive NF-κB activity in pancreatic cancer cells is maintained by a novel GSK-3-TAK1-IKK signaling cascade. These data broadens our understanding of NF-κB regulation in pancreatic cancer and implicates GSK-3 and TAK1 as emerging therapeutic targets

Maintenance of Constitutive I B Kinase Activity by Glycogen Synthase Kinase-3 / in Pancreatic Cancer

Constitutive NF-κB activation is among the many deregulated signaling pathways that are proposed to drive pancreatic cancer cell growth and survival. Recent reports suggest that glycogen synthase kinase-3β (GSK-3β) plays a key role in maintaining basal NF-κB target gene expression and cell survival in pancreatic cancer cell lines. However, the mechanism by which GSK-3β facilitates constitutive NF-κB signaling in pancreatic cancer remains unclear. In this report, we analyze the contributions of both GSK-3 isoforms (GSK-3α, GSK-3β) in regulating NF-κB activation and cell proliferation in pancreatic cancer cell lines (Panc-1 and MiaPaCa-2). We demonstrate that GSK-3 isoforms are differentially required to maintain basal NF-κB DNA binding activity, transcriptional activity, and cell proliferation in Panc-1 and MiaPaCa-2 cells. Our data also indicate that IKK subunits are not equally required to regulate pancreatic cancer-associated NF-κB activity and cell growth. Importantly, we provide the first evidence that GSK-3 maintains constitutive NF-κB signaling in pancreatic cancer by regulating IKK activity. These data provide new insight into GSK-3-dependent NF-κB regulation, and further establishes GSK-3 and IKK as potential therapeutic targets for pancreatic cancer

Billy Frank Jr. Plenary

Billy Frank Jr. Plenary Featuring: Debra Lekanoff Willie Frank III Ray Harris Murray Ned Chief Dalton Silver Lisa Wilson Glen Gobin Russ Heffne

Rapamycin Prevents the Development and Progression of Mutant Epidermal Growth Factor Receptor Lung Tumors with the Acquired Resistance Mutation T790M

Lung cancer in never-smokers is an important disease often characterized by mutations in epidermal growth factor receptor (EGFR), yet risk reduction measures and effective chemopreventive strategies have not been established. We identify mammalian target of rapamycin (mTOR) as potentially valuable target for EGFR mutant lung cancer. mTOR is activated in human lung cancers with EGFR mutations, and this increases with acquisition of T790M mutation. In a mouse model of EGFR mutant lung cancer, mTOR activation is an early event. As a single agent, the mTOR inhibitor rapamycin prevents tumor development, prolongs overall survival, and improves outcomes after treatment with an irreversible EGFR tyrosine kinase inhibitor (TKI). These studies support clinical testing of mTOR inhibitors in order to prevent the development and progression of EGFR mutant lung cancers

Transcending sovereignty : locating Indigenous peoples in transboundary water law

All people rely upon water for life. Indigenous peoples are especially vulnerable to water conflicts and yet lack recognition in international water law. This thesis adopts Critical Race Theory to examine the intersection between transboundary water law, the doctrine of sovereignty and the international law of Indigenous peoples. The methodology adopted in this thesis includes: (i) a deconstruction of the UN Watercourse Convention and the doctrine of sovereignty; (ii) a review of Indigenous perspectives on sovereignty; and (iii) a proposal for the reconstruction of transboundary water law in a manner that recognizes the internationally affirmed rights of Indigenous peoples. A deconstruction of the UN Watercourse Convention and related discourse reveals that state-centric approaches to transboundary water law fail to recognize Indigenous peoples’ international rights or the pivotal role that Indigenous peoples’ traditional knowledge might play in transcending conflict. Case examples are provided (Columbia River and Tsangpo-Brahmaputra River) that illustrate the vulnerability of Indigenous peoples in the face of state development agreements. The inequities that exist in international water law are rooted in the historical doctrine of sovereignty which has evolved to subordinate Indigenous peoples’ interests to state interests. Indigenous perspectives regarding sovereignty provide a counter-point to the dominant legal discourse and weave an alternate narrative that challenges the myth of objectivity and neutrality that surrounds the doctrine of sovereignty and international law generally. Once we recognize that sovereignty is a social construct, we can recognize our collective ability to reconstruct international laws in a manner that transcends the sovereign discourse and recognizes the rights of Indigenous peoples. Endorsement of the United Nations Declaration on the Rights of Indigenous Peoples (UNDRIP) is indicative of states’ commitment to recognize Indigenous peoples’ rights throughout the international legal system. This thesis concludes by offering a proposal for reconstructing transboundary water law through a return to ethics and coalition building. Future reform should be directed towards (a) articulating an international water ethic with the critical engagement of Indigenous peoples; and (b) ensuring that river basin organizations are established on every transboundary river in a manner consistent with this shared international water ethic.Law, Faculty ofGraduat