TPL2 kinase is a suppressor of lung carcinogenesis

Gkirtzimanaki, Katerina; Gkouskou, Kalliopi; Oleksiewicz, Urszula; Nikolaidis, George; Vyrla, Dimitra; Liontos, Michalis; Pelekanou, Vassiliki; Kanellis, Dimitris C.; Evangelou, Kostantinos; Stathopoulos, Efstathios N.; Field, John K.; Tsichlis, Philip N.; Gorgoulis, Vassilis G.; Liloglou, Triantafillos; Eliopoulos, Aristides G.

doi:10.1073/pnas.1215938110

Cited by 48 publications

(56 citation statements)

References 52 publications

(65 reference statements)

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“…55 For the colitis and CAC model, female C57BL/6J mice (approximately 18-20 g weight) were injected intaperitoneally with 10 mg/kg body weight AOM and 4 days later 2.5% DSS was administered in their drinking water for 5 days, followed by 14 days of regular water. This cycle was repeated once or three times more before mice were killed.…”

Section: Mice and In Vivo Treatmentsmentioning

confidence: 99%

“…For each animal, two sections approximately 400 μm apart were scored and averaged by an experienced pathologist (ED) blinded to the experimental conditions using a validated scoring system developed by Cooper et al 36 and Dieleman et al 57 and modified by Williams et al 58 in a scale of 0-40. IHC was performed as previously described 55 using the following antibodies applied overnight at 4°C: α-mouse ApoA-I (Meridian Life Science, Memphis, TN, USA, cat no. K23500R, used at 1:2000 dilution); α-phospho-Tyr 705 STAT3 (Cell Signaling, Danvers, MA, USA, cat no.…”

Section: Mice and In Vivo Treatmentsmentioning

confidence: 99%

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Apolipoprotein A-I inhibits experimental colitis and colitis-propelled carcinogenesis

et al. 2015

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In both humans with long-standing ulcerative colitis and mouse models of colitis-associated carcinogenesis (CAC), tumors develop predominantly in the distal part of the large intestine but the biological basis of this intriguing pathology remains unknown. Herein we report intrinsic differences in gene expression between proximal and distal colon in the mouse, which are augmented during dextran sodium sulfate (DSS)/azoxymethane (AOM)-induced CAC. Functional enrichment of differentially expressed genes identified discrete biological pathways operating in proximal vs distal intestine and revealed a cluster of genes involved in lipid metabolism to be associated with the disease-resistant proximal colon. Guided by this finding, we have further interrogated the expression and function of one of these genes, apolipoprotein A-I (ApoA-I), a major component of high-density lipoprotein. We show that ApoA-I is expressed at higher levels in the proximal compared with the distal part of the colon and its ablation in mice results in exaggerated DSS-induced colitis and disruption of epithelial architecture in larger areas of the large intestine. Conversely, treatment with an ApoA-I mimetic peptide ameliorated the phenotypic, histopathological and inflammatory manifestations of the disease. Genetic interference with ApoA-I levels in vivo impacted on the number, size and distribution of AOM/DSS-induced colon tumors. Mechanistically, ApoA-I was found to modulate signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB activation in response to the bacterial product lipopolysaccharide with concomitant impairment in the production of the pathogenic cytokine interleukin-6. Collectively, these data demonstrate a novel protective role for ApoA-I in colitis and CAC and unravel an unprecedented link between lipid metabolic processes and intestinal pathologies.

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Section: Mice and In Vivo Treatmentsmentioning

confidence: 99%

Section: Mice and In Vivo Treatmentsmentioning

confidence: 99%

Apolipoprotein A-I inhibits experimental colitis and colitis-propelled carcinogenesis

et al. 2015

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“…57 To test the hypothesis that TPL2 is essential for MAM activation and myeloma progression, we crossed Tpl2 2/2 animals 41 to the genetically engineered myeloma model, Vk*MYC. 58,59 Following its initial discovery as an oncogene, 60 Tpl2 has been shown to variably act as a tumor promoter or suppressor gene in various models of solid tumors, [61][62][63][64][65][66][67][68][69][70][71] Figure 4C). By contrast, the rates of apoptosis (cleaved caspase 3 positivity) in CD138 1 cells from tumor-matched animals were low and not significantly different between the 2 genotypes ( Figure 4D).…”

Section: Tpl2 a "Druggable" Map3kinase Downstream Of Tlrs Controls mentioning

confidence: 99%

TPL2 kinase regulates the inflammatory milieu of the myeloma niche

Hope

Ollar

Héninger

et al. 2014

Blood

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“…In contrast to its function in urogenital tumors, Tpl2 acts as a tumor suppressor gene in lung carcinogenesis through p53 response to genotoxic stress. 47 Therefore, Tpl2 exerts its unique functions according to the characteristic molecular environments of biological systems. Specifically, in urogenital cancers, Tpl2 acts as a principal driver of the progression and metastasis by activating FAK/Akt and CXCL12/ CXCR4 signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Tpl2 induces castration resistant prostate cancer progression and metastasis

Lee

Cho

Lee

et al. 2014

Intl Journal of Cancer

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Progression to metastatic castration resistant prostate cancer (CRPC) is the major lethal pathway of prostate cancer (PC). Herein, we demonstrated that tumor progression locus 2 (Tpl2) kinase is the fundamental molecule provoking progression and metastasis of CRPC. Tpl2 upregulates CXCR4 and focal adhesion kinase (FAK) to activate CXCL12/CXCR4 and FAK/Akt signalling pathway. Consequently, epithelial-mesenchymal transition (EMT) and stemness of androgen depletion independent (ADI) PC cells are induced, which is dependent on the kinase activity of Tpl2. In vitro, proliferation, clonogenicity, migration, invasion and chemoresistance of ADI PC cells were enhanced by Tpl2. In vivo, Tpl2 overexpression and downregulation showed significant stimulatory and inhibitory effects on tumorigenic and metastatic potential of ADI PC cells, respectively. Moreover, the prognostic effects of Tpl2 and expressional correlation between Tpl2 and EMT-related molecules/CXCR4 were validated in clinical PC databases. Since Tpl2 exerts metastatic progression promoting activities in CRPC, Tpl2 could serve as a novel therapeutic target for metastatic CRPC.Prostate cancer (PC) is the most common cancer and second leading cause of cancer-related deaths in males in the United States. 1 Although androgen depletion therapy is highly effective in suppressing PC growth, persistent androgen ablation often results in the development of metastatic castration resistant prostate cancer (CRPC). 2 Currently, patients with metastatic CRPC are treated with taxane-based chemotherapeutic drugs. However, the treatment only serves as a palliative, and distant metastasis is the main cause of PC-related death. 3 Therefore, the identification of novel therapeutic targets in metastatic CRPC is the most urgent clinical requirement that remains unmet.Tumors contain a reservoir of cancer stem cells (CSCs) that are responsible for tumor initiation, progression, metastasis and therapeutic resistance. 4 Since emerging evidence suggests that PC CSCs represent the "bad seeds" of tumor, the molecular mechanisms that maintain PC CSCs could potentially serve as therapeutic targets for metastatic CRPC. 5,6 Although aldehyde dehydrogenase (ALDH) activity 7 and expression of CD44 8 and Bmi-1 9 have been suggested as specific PC CSC markers, using these markers as therapeutic targets is challenging because the molecules lack specific functional and/or enzymatic activities.Tumor progression locus 2 [Tpl2/MAP3 kinase 8 (MAP3K8)], a serine/threonine protein kinase, has been suggested to enhance tumor growth and metastatic progression in distinct types of human cancers. 10-12 Previously, we

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TPL2 kinase is a suppressor of lung carcinogenesis

Cited by 48 publications

References 52 publications

Apolipoprotein A-I inhibits experimental colitis and colitis-propelled carcinogenesis

Apolipoprotein A-I inhibits experimental colitis and colitis-propelled carcinogenesis

TPL2 kinase regulates the inflammatory milieu of the myeloma niche

Tpl2 induces castration resistant prostate cancer progression and metastasis

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