TAK1 regulates the tumor microenvironment through inflammatory, angiogenetic and apoptotic signaling cascades

Oncotarget
Scott A ScarneoTimothy A J Haystead

Abstract

Transforming growth factor beta-activated kinase 1 (TAK1) has been implicated for its role in inflammatory signaling and as an important mediator of cellular apoptosis and necroptosis in various cell types. Our recent discovery of a first-in-class, potent and selective TAK1 inhibitor, takinib, represents a novel pharmacological tool to evaluate TAK1's role in cancer. In this study we evaluated the potential therapeutic capacity of TAK1 inhibition on tumor growth and on tumor microenvironment remodeling. In a screen of 16 cancer cell lines, takinib in combination with tumor necrosis factor (TNF) was found to induce cell death (>20%) in 6 out of 16 cell lines. Furthermore, knocking out of TAK1 in MDA-MB-231 cells dramatically increased their sensitization to TNF-mediated apoptosis. In vivo xenographs of MDA-MB-231 TAK1KO tumors displayed delayed tumor growth and increased overall survival compared to TAK1WT controls. Histological and proteomic analysis of TAK1KO tumors showed altered angiogenic signaling and inflammatory signaling via immune cells. Overall, these findings suggest that the targeting of TAK1 in immune mediated cancers may be a novel therapeutic axis.

References

Feb 28, 2002·Molecular and Cellular Biology·M Germana SannaRichard J Ulevitch
Aug 27, 2004·Nature·Eli PikarskyYinon Ben-Neriah
May 6, 2006·The Journal of Biological Chemistry·Emily OmoriJun Ninomiya-Tsuji
Aug 24, 2006·Breast Cancer Research and Treatment·Heike Knüpfer, Rainer Preiss
Jul 3, 2009·Cell Cycle·Jiang Yang, Marsha A Moses
Feb 18, 2010·Proceedings of the National Academy of Sciences of the United States of America·Michael A CurranJames P Allison
Feb 22, 2012·Cell·Anurag SinghJeff Settleman
Jul 17, 2012·Trends in Pharmacological Sciences·Hiroaki Sakurai
May 15, 2013·Trends in Immunology·Adebusola A AjibadeRong-Fu Wang
Oct 25, 2013·Nature Reviews. Cancer·Eran ElinavRichard A Flavell
Feb 19, 2014·The Journal of Cell Biology·Sho MoriokaJun Ninomiya-Tsuji
Sep 15, 2015·Biochimica Et Biophysica Acta·Amit WaliaDimitri T Azar
Nov 13, 2015·American Journal of Clinical Oncology·Elizabeth I Buchbinder, Anupam Desai
Apr 25, 2018·Nature Medicine·Mikhail BinnewiesMatthew F Krummel
Aug 1, 2018·International Journal of Molecular Sciences·Josiah OchiengPhilip Lammers
Jan 11, 2020·Frontiers in Oncology·Meng-Ya ZhangJie Guo

❮ Previous
Next ❯

Citations

Sep 3, 2020·Open Biology·Juliane TotzkeTimothy A J Haystead
Aug 28, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Biswadeep DasAkash Agnihotri

❮ Previous
Next ❯

Methods Mentioned

BETA
protein array
xenografts
PMA
transfection

Software Mentioned

GraphPad Prism

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Allergy and Asthma

Allergy and asthma are inflammatory disorders that are triggered by the activation of an allergen-specific regulatory t cell. These t cells become activated when allergens are recognized by allergen-presenting cells. Here is the latest research on allergy and asthma.

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.