Modulation of Pancreatic Cancer Chemoresistance by Inhibition of TAK1

Melisi, Davide; Xia, Qianghua; Paradiso, Genni; Ling, Jianhua; Moccia, Tania; Carbone, Carmine; Budillon, Alfredo; Abbruzzese, James L.; Chiao, Paul J.

doi:10.1093/jnci/djr243

Cited by 141 publications

(136 citation statements)

References 47 publications

Supporting

Mentioning

131

Contrasting

Unclassified

Order By: Relevance

“…We next sought to identify proteins selectively thiophosphorylated by AS-TAK1 f in lysates from four cell lines from two cancer types, colorectal (CaCo2, SW620) and pancreatic (PC3, DU145). These cell lines were selected because TAK1 has been shown to be particularly important in colorectal and prostate cancers (18,19). Lysates were individually labeled by spiking in N 6 -furfuryl-ATPγS and purified AS-TAK1 f , WT-TAK1 f , or with no added kinase.…”

Section: Resultsmentioning

confidence: 99%

Innate immunity kinase TAK1 phosphorylates Rab1 on a hotspot for posttranslational modifications by host and pathogen

Levin

Hertz

Burlingame

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

TGF-β activated kinase 1 (TAK1) is a critical signaling hub responsible for translating antigen binding signals to immune receptors for the activation of the AP-1 and NF-κB master transcriptional programs. Despite its importance, known substrates of TAK1 are limited to kinases of the MAPK and IKK families and include no direct effectors of biochemical processes. Here, we identify over 200 substrates of TAK1 using a chemical genetic kinase strategy. We validate phosphorylation of the dynamic switch II region of GTPase Rab1, a mediator of endoplasmic reticulum to Golgi vesicular transport, at T75 to be regulated by TAK1 in vivo. TAK1 preferentially phosphorylates the inactive (GDP-bound) state of Rab1. Phosphorylation of Rab1 disrupts interaction with GDP dissociation inhibitor 1 (GDI1), but not guanine exchange factor (GEF) or GTPaseactivating protein (GAP) enzymes, and is exclusive to membranelocalized Rab1, suggesting phosphorylation may stimulate Rab1 membrane association. Furthermore, we found phosphorylation of Rab1 at T75 to be essential for Rab1 function. Previous studies established that the pathogen Legionella pneumophila is capable of hijacking Rab1 function through posttranslational modifications of the switch II region. Here, we present evidence that Rab1 is regulated by the host in a similar fashion, and that the innate immunity kinase TAK1 and Legionella effectors compete to regulate Rab1 by switch II modifications during infection.

show abstract

Section: Resultsmentioning

confidence: 99%

Innate immunity kinase TAK1 phosphorylates Rab1 on a hotspot for posttranslational modifications by host and pathogen

Levin

Hertz

Burlingame

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…In addition, CXCR4 signaling regulated by NF-kB has also been reported serving as a counter defense mechanism against gemcitabine in PDAC (10), which is most like another parallel pathway regulated by NF-kB. Our previous studies showed that PDAC cells with silenced TAK1 had lower NF-kB activity and were more sensitive to gemcitabine, suggesting that activation of NF-kB played an important role in chemoresistance (20).…”

Section: Discussionmentioning

confidence: 95%

“…All mice were weighed every 5 days and observed for tumor growth. Bioluminescence imaging of tumors was conducted using a cryogenically cooled IVIS 100 imaging system as previously described (20). The day after the end of treatment, the mice were euthanized by carbon dioxide inhalation and the tumors were excised and weighed.…”

Section: Animal Studymentioning

confidence: 99%

See 1 more Smart Citation

Mechanisms of Overcoming Intrinsic Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma through the Redox Modulation

Gocho

Aguilar

et al. 2015

Molecular Cancer Therapeutics

Self Cite

117

111

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) frequently develops therapeutic resistances, which can be divided into extrinsic and intrinsic resistance. The extrinsic resistance that arises from the surrounding dense tumor stroma is much better understood. However, the mechanisms of intrinsic resistance are not well understood. Here, we report that reactive oxygen species (ROS) induced by gemcitabine treatment, a newly discovered cytotoxic activity, served as a probe in our study to reveal the mechanisms of the intrinsic therapeutic resistance. Our results showed that gemcitabine-induced ROS is generated by NOX and through the increase of p22 -phox expression via NF-kB activation. As a feedback mechanism, nuclear translocation of Nrf2 stimulated the transcription of cytoprotective antioxidant genes, especially genes encoding enzymes that catalyze glutathione (GSH) production to reduce elevated ROS as an intrinsic resistance countermeasure. RNAi-mediated depletion of Nrf2 or addition of b-phenylethyl isothiocyanate inhibited the ROS detoxification process by reducing GSH levels, which, in turn, increased the efficacy of gemcitabine in vitro and in vivo. Thus, our study suggests that a redoxmediated pathway contributes to the intrinsic resistance of PDAC to gemcitabine and provides a basis for developing strategies to preferentially kill PDAC cells through ROS-mediated mechanism. The combination of gemcitabine and PEITC has a selective cytotoxic effect against pancreatic cancer cells in vivo and could thus prove valuable as a cancer treatment. Mol Cancer Ther; 14(3); 788-98.Ó2014 AACR.

show abstract

“…For instance, overexpression of TAK1 could promote the tumor growth and metastatic capacity of ovarian cancer cells by enhancing NF-kB transactivity (11). However, deletion of the TAK1 gene in skin tumors induces tumor cell apoptosis, and inhibition of TAK1 kinase activity leads to a proapoptotic phenotype and reverts the intrinsic chemoresistance of pancreatic cancer (12,13), suggesting that targeting TAK1 might be a promising and effective therapeutic approach to counteract tumor progression. In addition, TAB3, the key factor of the TAK1/TAB2/3 complex, is markedly elevated in a variety of cancers (14), and silencing either TAK1 or TAB3 could enhance the rates of doxorubicin-induced apoptosis and the chemosensitivity of hepatocellular carcinoma cells (15).…”

Section: Introductionmentioning

confidence: 99%

miR-892b Silencing Activates NF-κB and Promotes Aggressiveness in Breast Cancer

Jiang

Zhang

et al. 2016

Cancer Research

View full text Add to dashboard Cite

The strength and duration of NF-kB signaling is tightly controlled at multiple levels under physiologic conditions, but the mechanism underlying constitutive activation of the NF-kB pathway in cancer remains unclear. In this study, we investigated miRNA-mediated regulation of the NF-kB cascade in breast cancer. We report that miR-892b expression was significantly downregulated in human breast cancer specimens and correlated with poor patient survival. Overexpression of miR-892b in breast cancer cells significantly decreased tumor growth, metastatic capacity, and the ability to induce angiogenesis, whereas miR-892b depletion enhanced these properties, in vitro and in vivo. Furthermore, we demonstrate that miR-892b attenuated NF-kB signaling by directly targeting and suppressing multiple mediators of NF-kB, including TRAF2, TAK1, and TAB3, and thus, miR-892b silencing in breast cancer cells sustains NF-kB activity. Moreover, miR-892b downregulation was attributed to aberrant hypermethylation of its promoter. Taken together, our results provide insight into a new mechanism by which NF-kB signaling becomes constitutively activated in breast cancer and suggest a tumor-suppressive role for miR-829b, prompting further investigation into miRNA mimics for cancer therapy.

show abstract

Modulation of Pancreatic Cancer Chemoresistance by Inhibition of TAK1

Abstract: The results of this study suggest that genetic silencing or inhibition of TAK1 kinase activity in vivo is a potential therapeutic approach to reversal of the intrinsic chemoresistance of pancreatic cancer.

Cited by 141 publications

References 47 publications

Innate immunity kinase TAK1 phosphorylates Rab1 on a hotspot for posttranslational modifications by host and pathogen

Innate immunity kinase TAK1 phosphorylates Rab1 on a hotspot for posttranslational modifications by host and pathogen

Mechanisms of Overcoming Intrinsic Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma through the Redox Modulation

miR-892b Silencing Activates NF-κB and Promotes Aggressiveness in Breast Cancer

Contact Info

Product

Resources

About