Modulating TAK1 Expression Inhibits YAP and TAZ Oncogenic Functions in Pancreatic Cancer

Abstract

YAP and TAZ are central determinants of malignancy; however, their functions remain still undruggable. We identified TGFb-activated kinase 1 (TAK1) as a central hub integrating the most relevant signals sustaining pancreatic cancer aggressiveness and chemoresistance. Glycogen synthase kinase (GSK)3 is known to stabilize TAK1, and its inhibition causes a reduction in TAK1 levels. Here, we hypothesized that TAK1 could sustain YAP/TAZ program, and thus, modulation of TAK1 expression through the inhibition of GSK3 could impair YAP/TAZ functions in pancreatic cancer. Differentially expressed transcripts between pancreatic cancer cells expressing scramble or TAK1-specific shRNA were annotated for functional interrelatedness by ingenuity pathway analysis. TAK1 expression was modulated by using different GSK3 inhibitors, including LY2090314. In vivo activity of LY2090314 alone or in combination with nab-paclitaxel was evaluated in an orthotopic nude mouse model. Differential gene expression profiling revealed significant association of TAK1 expression with HIPPO and ubiquitination pathways. We measured a significant downregulation of YAP/TAZ and their regulated genes in shTAK1 cells. TAK1 prevented YAP/TAZ proteasomal degradation in a kinase independent manner, through a complex with TRAF6, thereby fostering their K63-ubiquitination versus K48ubiquitination. Pharmacologic modulation of TAK1 by using GSK3 inhibitors significantly decreased YAP/TAZ levels and suppressed their target genes and oncogenic functions. In vivo, LY2090314 plus nab-paclitaxel significantly prolonged mice survival duration. Our study demonstrates a unique role for TAK1 in controlling YAP/TAZ in pancreatic cancer. LY2090314 is a novel agent that warrants further clinical development in combination with nab-paclitaxel for the treatment of pancreatic cancer.

Targeting cancer stem cells in cholangiocarcinoma (Review)

“…2). It has been shown that LY2090314 treatment in conjunction with nab-paclitaxel in a preclinical model of pancreatic cancer prolonged mice survival (82). However, regimens consisting of LY2090314 in combination with pemetrexed and carboplatin, demonstrated suboptimal safety profiles and minimal clinical efficacy in patients with advanced pancreatic cancer in a previous phase I clinical trial (83).…”

Plasma IL8 Is a Biomarker for TAK1 Activation and Predicts Resistance to Nanoliposomal Irinotecan in Patients with Gemcitabine-Refractory Pancreatic Cancer

“…GSE137265) were examined by using Illumina Human 48k gene chips (D-103-0204; Illumina) as previously described in ref. 9.…”

“…We recently identified the serine/threonine kinase TGFb-activated kinase 1 (TAK1) as a central hub integrating the most relevant signals from various cytokines (5,6) and sustaining, in turn, resistance to chemotherapeutic treatments through the activation of different transcription factors, including AP-1, NF-kB (7,8), and YAP/TAZ (9). In particular, we demonstrated that targeting the kinase activity of TAK1 dramatically led to a proapoptotic phenotype and, in turn, to a significantly higher sensitivity to chemotherapy and radiotherapy in pancreatic (10) and esophageal carcinoma (11).…”

Yap Promotes Epithelial Cell Proliferation and Epithelium-derived Innate Cytokine Expression via the NF-κb Pathway in Chronic Rhinosinusitis With Nasal Polyps

“…One study showed that TAK1 mediated YAP phosphorylation, resulting in a reciprocal antagonism between Hippo-YAP/TAZ and NF-κB signalling during osteoarthritis pathogenesis (Deng et al, 2018). The other study showed that TAK1 regulated YAP-derived oncogenicity in pancreatic cancer (Santoro et al, 2020). Further studies are warranted to characterize the exact regulated mechanism of YAP and NF-κB in the regulation of in ammatory cell functions in nasal polyps to nd out if there was a bi-directional control mechanism.…”