American Association for Cancer Research
21598290cd120541-sup-fig9.pdf (263.26 kB)

Supplementary Figure 9 from GSK-3α Promotes Oncogenic KRAS Function in Pancreatic Cancer via TAK1–TAB Stabilization and Regulation of Noncanonical NF-κB

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journal contribution
posted on 2023-04-03, 20:43 authored by Deepali Bang, Willie Wilson, Meagan Ryan, Jen Jen Yeh, Albert S. Baldwin

PDF file - 263K, Kras regulates GSK-3α mRNA levels. HKRAS cells were transiently transfected with non-targeting control or KRAS siRNA. RNA was isolated, reverse transcribed to cDNA and real time RT-PCR performed for Kras and GSK-3α. Gus B was used as endogenous control.



Mutations in KRAS drive the oncogenic phenotype in a variety of tumors of epithelial origin. The NF-κB transcription factor pathway is important for oncogenic RAS to transform cells and to drive tumorigenesis in animal models. Recently, TGF-β–activated kinase 1 (TAK1), an upstream regulator of IκB kinase (IKK), which controls canonical NF-κB signaling, was shown to be important for chemoresistance in pancreatic cancer and for regulating KRAS-mutant colorectal cancer cell growth and survival. Here, we show that mutant KRAS upregulates glycogen synthase kinase 3α (GSK-3α), leading to its interaction with TAK1 to stabilize the TAK1–TAB complex to promote IKK activity. In addition, GSK-3α is required for promoting critical noncanonical NF-κB signaling in pancreatic cancer cells. Pharmacologic inhibition of GSK-3 suppresses growth of human pancreatic tumor explants, consistent with the loss of expression of oncogenic genes such as c-myc and TERT. These data identify GSK-3α as a key downstream effector of oncogenic KRAS via its ability to coordinately regulate distinct NF-κB signaling pathways.Significance: GSK-3α functions to promote IKK/NF-κB activity downstream of oncogenic KRAS via stabilization and activation of the TAK1/TAB complex and to promote noncanonical NF-κB activity via control of nuclear levels of NF-κB2. Inhibition of GSK-3 strongly suppresses growth of human pancreatic tumor explants with downregulation of certain oncogenic NF-κB target genes such as c-myc and TERT. Cancer Discov; 3(6); 690–703. ©2013 AACR.This article is highlighted in the In This Issue feature, p. 591