Triterpenoid CDDO-Methyl Ester Inhibits the Janus-Activated Kinase-1 (JAK1)→Signal Transducer and Activator of Transcription-3 (STAT3) Pathway by Direct Inhibition of JAK1 and STAT3

Ahmad, Rehan; Raina, Deepak; Meyer, Colin; Küfe, Donald

doi:10.1158/0008-5472.can-07-3036

Cited by 106 publications

(98 citation statements)

References 42 publications

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“…16 The proposed mechanism underlying the anticancer effects of SOs is by the formation of Michael adducts between SOs and reactive nucleophiles, such as free thiols on target proteins. [17][18][19][20] The wide spectrum of SO effects is explained, in part, by their concentration-dependent induction of oxidative stress, which alters various redox-sensitive proteins and signaling networks. SOs show unique promise in the prevention and treatment of cancer, 16 and may also act synergistically with other anticancer agents to induce stress overload and/or stress sensitization.…”

mentioning

confidence: 99%

The mitochondrial ATP-dependent Lon protease: a novel target in lymphoma death mediated by the synthetic triterpenoid CDDO and its derivatives

Bernstein

Venkatesh

et al. 2012

Blood

128

125

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Synthetic triterpenoids are multitarget compounds exhibiting promise as preventative and therapeutic agents for cancer. Their proposed mechanism of action is by forming Michael adducts with reactive nucleophilic groups on target proteins. Our previous work demonstrates that the 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its derivatives promote B-lymphoid cell apoptosis through a mitochondria-mediated pathway linked to mitochondrial protein aggregation. As one function of the Lon protease is to eliminate abnormal mitochondrial proteins, we hypothesized that CDDO-induced protein aggregation and lymphoma apoptosis occur by inactivating this enzyme. Here, we show that CDDO and its derivatives directly and selectively inhibit Lon. CDDO blocks Lon-mediated proteolysis in biochemical and cellular assays, but does not inhibit the 20S proteasome. Furthermore, a biotinylated-CDDO conjugate modifies mitochondrial Lon. A striking common phenotype of CDDO-treated lymphoma cells and Lon-knockdown cells is the accumulation of electron-dense aggregates within mitochondria. We also show that Lon protein levels are substantially elevated in malignant lymphoma cells, compared with resting or activated B cells. Finally, we demonstrate that Lon knockdown leads to lymphoma cell death. Together, these findings suggest that Lon inhibition plays a contributory role in CDDO-induced lymphoma cell death, and support the concept that mitochondrial Lon is a novel anticancer drug target. IntroductionThe malignant transformation of normal cells into cancer cells is driven principally by enhanced oncogenic protein function and/or inactivation of tumor suppressors. To promote this transformation process, tumor cells undergo an extensive reprogramming of normal growth and survival pathways that are mediated by nononcogenic proteins. The identification of nononcogenic proteins that are essential for the survival and proliferation of cancer cells provides potential new drug targets for anticancer therapeutics. Nononcogenic proteins participating in the cell stress response have emerged as a unique and important class of viable targets. Recent work demonstrates that pharmacologic inhibition or downregulation of the master transcriptional regulator of the cell stress response-heat shock factor 1 (HSF1), 1 as well as of the molecular chaperones HSP70 or HSP90, selectively inhibit tumor development. 2,3 Remarkably, the inhibition or down-regulation of these essential heat-shock response proteins effectively limits cancer cell growth without substantially compromising normal cell survival. 1,2,4 Luo and colleagues 6 have expanded on the classic hallmarks of cancer originally proposed by Hanahan and Weinberg 5 to include several common stress phenotypes of tumorigenesis. The neoplastic transformation of cancer cells gives rise to diverse oncogenic stressors such as DNA damage and mitotic stress, as well as to metabolic, proteotoxic, and oxidative stress. Cancer cells thus depend on conserved defense mechanisms to survive such oncogenic str...

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mentioning

confidence: 99%

The mitochondrial ATP-dependent Lon protease: a novel target in lymphoma death mediated by the synthetic triterpenoid CDDO and its derivatives

Bernstein

Venkatesh

et al. 2012

Blood

128

125

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“…CDDOMe was shown to inhibit IKKa kinase and subsequently IjBa protein phosphorylation and degradation, as well as NF-jB-dependent transactivation of the reporter gene [163]. Furthermore, both CDDO-Me and CDDO-Im could inhibit IKKb kinase by directly binding to Cys-179 and inhibiting the enzymatic activity of IKKb [164][165][166]. Sohn et al provided first evidence that OA have antiangiogenic effects on bovine aortic endothelial cells and in chick embryo chorioallantoic membrane assay [167].…”

Section: Oleanolic Acidmentioning

confidence: 99%

“…In many instances, it has been observed that these compounds bind to the active cysteine residue in the proteins [16]. The key proteins that have been reported to be modulated by oleanane triterpenoids are Keap 1 [193,194], IKK, IkBa and NF-jB [164,166], JAK1 and STAT3 [165,195,196], PTEN [197], AKT [14,198,199], mTOR [200], ROS [201], DR5 and CHOP [202], GSK3b [203], cFLIP and VEGF [204,205], mitochondrial membrane potential [206], and cell cycle arrest [198,207,208]. In another study where transgenic LSL-Kras(G12D/+); LSL-Trp53(R127H/+); Pdx-1-Cre (KPC) mouse model of pancreatic cancer were fed with diet containing CDDO-Me or CDDO-ethyl amide, the rexinoid LG100268 significantly increased the survival of mice by 3-4 weeks [209] and prevented lung cancer development when fed with these terpenoids for 8 weeks [15].…”

Section: Synthetic Triterpenoidsmentioning

confidence: 99%

Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: Potential role in prevention and therapy of cancer

et al. 2012

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a b s t r a c tOver the last two decades, extensive research on plant-based medicinal compounds has revealed exciting and important pharmacological properties and activities of triterpenoids. Fruits, vegetables, cereals, pulses, herbs and medicinal plants are all considered to be biological sources of these triterpenoids, which have attracted great attention especially for their potent anti-inflammatory and anti-cancer activities. Published reports in the past have described the molecular mechanism(s) underlying the various biological activities of triterpenoids which range from inhibition of acute and chronic inflammation, inhibition of tumor cell proliferation, induction of apoptosis, suppression of angiogenesis and metastasis. However systematic analysis of various pharmacological properties of these important classes of compounds has not been done. In this review, we describe in detail the pre-clinical chemopreventive and therapeutic properties of selected triterpenoids that inhibit multiple intracellular signaling molecules and transcription factors involved in the initiation, progression and promotion of various cancers. Molecular targets modulated by these triterpenoids comprise, cytokines, chemokines, reactive oxygen intermediates, oncogenes, inflammatory enzymes such as COX-2, 5-LOX and MMPs, anti-apoptotic proteins, transcription factors such as NF-jB, STAT3, AP-1, CREB, and Nrf2 (nuclear factor erythroid 2-related factor) that regulate tumor cell proliferation, transformation, survival, invasion, angiogenesis, metastasis, chemoresistance and radioresistance. Finally, this review also analyzes the potential role of novel synthetic triterpenoids identified recently which mimic natural triterpenoids in physical and chemical properties and are moving rapidly from bench to bedside research.

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“…Inhibition of STAT3 was shown to have anticancer activity in vitro and in animal models (30)(31)(32)(33)(34). Furthermore, direct inhibition of GP130 attenuates STAT3 activation and inhibits some cancer cells (9).…”

Section: Introductionmentioning

confidence: 99%

Endogenous transmembrane protein UT2 inhibits pSTAT3 and suppresses hematological malignancy

Lee¹,

Wang²,

Kalaitzidis³

et al. 2016

Journal of Clinical Investigation

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Triterpenoid CDDO-Methyl Ester Inhibits the Janus-Activated Kinase-1 (JAK1)→Signal Transducer and Activator of Transcription-3 (STAT3) Pathway by Direct Inhibition of JAK1 and STAT3

Cited by 106 publications

References 42 publications

The mitochondrial ATP-dependent Lon protease: a novel target in lymphoma death mediated by the synthetic triterpenoid CDDO and its derivatives

The mitochondrial ATP-dependent Lon protease: a novel target in lymphoma death mediated by the synthetic triterpenoid CDDO and its derivatives

Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: Potential role in prevention and therapy of cancer

Endogenous transmembrane protein UT2 inhibits pSTAT3 and suppresses hematological malignancy

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