Activation of the JNK–AP-1 signal transduction pathway is associated with pathogenesis and progression of human osteosarcomas

Papachristou, Dionysios J.; Batistatou, Anna; Sykiotis, Gerasimos P.; Varakis, Ioannis; Papavassiliou, A. G.

doi:10.1016/s8756-3282(03)00026-7

Cited by 99 publications

(81 citation statements)

References 26 publications

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“…c-Fos is highly expressed in the vast majority of human OS 25 as well as in most of OS cell lines and its viral counterpart, v-Fos, up-regulates several key molecules in tumorigenesis/metastasis, including Ezrin. 42,43 Interestingly, Durchdewald et al recently reported that podoplanin is a novel c-Fos/AP-1 target gene.…”

Section: Discussionmentioning

confidence: 99%

“…Since overexpression of c-Fos in transgenic mice results in the formation of OS, 24 and since c-Fos was found to be up-regulated in a vast majority of human OS, 25 we next investigated its relevance to podoplanin expression in OS. First, we investigated whether exogenous c-Fos affected the expression of podoplanin using a subclone of murine MC3T3-E1 osteoblastic cells, AT9.2, which expresses c-Fos in a tetracycline (Tet)-regulatable manner (Tet-off system).…”

Section: C-fos Up-regulates Podoplanin Expression In Transformed Ostementioning

confidence: 99%

“…19,22,23 Particularly, we have shown previously that deregulated c-Fos expression in vivo causes osteosarcomas (OS) in mice 24 and high levels of c-Fos expression have been observed in the vast majority of human OS. 25 Although the role of podoplanin in platelet aggregation, cell migration, and metastasis of carcinoma cells is established, there has been one previous report in human OS cell lines suggesting that their ability to induce platelet aggregation in vitro might relate to their ability to metastasize. 26 We therefore postulated that podoplanin expression would be expressed in human OS in vivo and involved in OS metastasis.…”

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confidence: 99%

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Podoplanin Is Regulated by AP-1 and Promotes Platelet Aggregation and Cell Migration in Osteosarcoma

Kunita

Kashima

Ohazama

et al. 2011

The American Journal of Pathology

100

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Podoplanin is a type-I transmembrane sialomucinlike protein, which is expressed in a wide range of cell types and is involved in platelet aggregation and tumor metastasis. Here, we investigated the function, regulation, and expression of podoplanin in osteosarcoma. Podoplanin expression was observed in three osteosarcoma cell lines (MG-63, HOS, and U-2 OS) with platelet aggregation-inducing ability, which was blocked by podoplanin small-interfering RNA or a neutralizing antibody. Overexpression of podoplanin in nonmetastatic Dunn osteosarcoma cells promoted cell migration without attenuating cell proliferation. Both podoplanin and TGF-␤1 were up-regulated by c-Fos induction in MC3T3-E1 osteoblastic cells, and were highly expressed in c-Fos transgenic mouse osteosarcomas and c-Fos-transformed osteosarcoma cell lines. Immunohistochemistry of human osteosarcoma tissue microarrays (n ‫؍‬ 133) showed staining of tumor cells embedded in an excess of irregular neoplastic bone matrix in 100% of tumors undergoing so-called "normalization/maturation." Podoplanin was also expressed in osteosarcoma subtypes, with 65% of osteoblastic, 100% of chondroblastic, and 79% of fibroblastic tumors. CD44 and pERM immunohistochemistry showed coexpression with podoplanin in both mouse and human osteosarcoma. Podoplanin expression was significantly higher in metastatic osteosarcomas (n ‫؍‬ 6) than in primary osteosarcomas (n ‫؍‬ 10). Our data suggest that podoplanin, which is not expressed in normal osteoblasts but in osteocytes, is aberrantly expressed in transformed osteoblasts and in osteosarcoma, and is under AP-1 transcriptional control. Thus podoplanin is a candidate molecule for ther- Osteosarcoma (OS) is the most common primary malignant bone tumor, with a high tendency to metastasize to the lung. Despite recent advances in modern chemotherapy, the average survival after a recurrence in distant organs is less than 1 year.1 In contrast, of patients who present with no metastasis, approximately 70% will be long-term survivors.2 Therefore, there is a strong necessity to better understand the molecular mechanisms of metastasis to deliver innovative life-saving and life-enhancing therapies to patients.Platelet aggregation is one of the crucial steps involved during the sequential tumor metastasis process to escape from the host immune system and form tumor emboli in distant organs. Several earlier studies have shown that platelet aggregating capability of tumor cells from colon cancer and melanoma is correlated with their metastatic potential in vivo.3-5 Podoplanin, a type-I transmembrane sialomucin-like glycoprotein, is a platelet aggregation-inducing factor 6 that is expressed in a wide range of tumors 7-9 and has been reported to be associated with poor outcome of oral and esophageal squamous cell carcinomas.10,11 Podoplanin promotes cell migration and cell invasion, 9,12 and also plays a key role in epithelial-mesenchymal transition in Madin-Darby canine kidney (MDCK) type-II cells.

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Section: Discussionmentioning

confidence: 99%

Section: C-fos Up-regulates Podoplanin Expression In Transformed Ostementioning

confidence: 99%

mentioning

confidence: 99%

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Podoplanin Is Regulated by AP-1 and Promotes Platelet Aggregation and Cell Migration in Osteosarcoma

Kunita

Kashima

Ohazama

et al. 2011

The American Journal of Pathology

100

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“…Western blot analysis revealed that at 12 h, rIL-10 could induce significantly higher expression of p-PI3K, p-Akt, and p-JNK, whereas Sb R LD failed to show expression of any of these molecules. It has been reported previously that phosphorylation of JNK leads to activation of different activator protein-1 (AP-1) subunits (19). Interestingly, our result also showed activation of AP-1 (c-Fos and c-Jun; P < 0.001) on rIL-10 treatment at 12 h, whereas other AP-1 subunits like Fra-1, Jun B, and Jun D were absent in the nuclear extract irrespective of the nature of the infection or rIL-10 treatment.…”

Section: Sb R Ld Drives Host Mϕs To Produce Il-10 Through Their Terminalmentioning

confidence: 99%

Antimony-resistant but not antimony-sensitiveLeishmania donovaniup-regulates host IL-10 to overexpress multidrug-resistant protein 1

Mukherjee

Mukhopadhyay

Bannerjee

et al. 2013

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

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The molecular mechanism of antimony-resistant Leishmania donovani (Sb R LD)-driven up-regulation of IL-10 and multidrug-resistant protein 1 (MDR1) in infected macrophages (Mϕs) has been investigated. This study showed that both promastigote and amastigote forms of Sb R LD, but not the antimony-sensitive form of LD, express a unique glycan with N-acetylgalactosamine as a terminal sugar. Removal of it either by enzyme treatment or by knocking down the relevant enzyme, galactosyltransferase in Sb R LD (KD Sb R LD), compromises the ability to induce the above effects. Infection of Mϕs with KD Sb R LD enhanced the sensitivity toward antimonials compared with infection with Sb R LD, and infection of BALB/c mice with KD Sb R LD caused significantly less organ parasite burden compared with infection induced by Sb R LD. The innate immune receptor, Toll-like receptor 2/6 heterodimer, is exploited by Sb R LD to activate ERK and nuclear translocation of NF-κB involving p50/c-Rel leading to IL-10 induction, whereas MDR1 up-regulation is mediated by PI3K/Akt and the JNK pathway. Interestingly both recombinant IL-10 and Sb R LD up-regulate MDR1 in Mϕ with different time kinetics, where phosphorylation of PI3K was noted at 12 h and 48 h, respectively, but Mϕs derived from IL-10 −/− mice are unable to show MDR1 up-regulation on infection with Sb R LD. Thus, it is very likely that an IL-10 surge is a prerequisite for MDR1 up-regulation. The transcription factor important for IL-10-driven MDR1 up-regulation is c-Fos/c-Jun and not NF-κB, as evident from studies with pharmacological inhibitors and promoter mapping with deletion constructs.visceral leishmaniasis | antimony resistance | glycoconjugate | antimony efflux K ala-azar or visceral leishmaniasis, which is caused by the protozoan parasite Leishmania donovani (LD), is (re)emerging and spreading worldwide, essentially because of humanmade and environmental changes, immunosuppression, and drug resistance (1, 2). To combat the disease, organic pentavalent antimonials were introduced in the Indian subcontinent almost 9 decades ago (3) with dramatic clinical success. However, the toxicity, together with the high treatment failure rate (up to 65%) and the emergence of resistance in Bihar State, India, made the drug obsolete in the Indian subcontinent (4, 5). Nevertheless, it is still used as a first-line treatment in Africa and Latin America (6). Interestingly, 78% of the recent clinical isolates from the hyperendemic zone of Bihar State still showed in vitro resistance to antimonials (7), which might be explained by an increased fitness of the corresponding parasites (8).Recently, we have demonstrated three unique characteristics of antimony-resistant LD (Sb R LD). First, it shows a higher concentration of terminal glycoconjugates (N-acetylgalactosamine residues) on its surface than antimony-sensitive LD (Sb S LD) (7).Second, on infection of macrophages (Mϕs), Sb R LD induces a surge of IL-10 (7, 9). Third, we also observed that Sb R LD modulates host cells to overexpress the ATP-b...

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“…It has also been reported that αNAC is expressed in malignant brain tumor cells (19). Papachristou et al showed that αNAC was expressed in osteosarcoma, but not in normal bone, and was expressed more strongly in high grade tumors compared with low grade tumors on immunohistochemical analysis (31). αNAC is involved in a coactivator potentiating c-Jun-mediated transcription process (20,33,34).…”

Section: Referencesmentioning

confidence: 97%

Increased alpha-taxilin protein expression is associated with the metastatic and invasive potential of renal cell cancer

et al. 2011

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Intracellular vesicle trafficking is the principal transportation system in eukaryotic cells, and is considered to be involved in a variety of processes related to cell proliferation. A protein named alpha-taxilin has been identified as a binding partner of the syntaxin family, which coordinates intracellular vesicle trafficking. To clarify the role of alpha-taxilin in renal cell carcinoma (RCC), we investigated alpha-taxilin protein expression in clear cell RCC tissues. We analyzed alphataxilin protein in matched sets of tumor and non-tumor tissues from the surgical specimens of 52 Japanese RCC patients by Western blotting. We also studied the relation between alpha-taxilin protein expression in tumor tissues and various clinicopathological features. The alpha-taxilin protein level was higher in tumor tissues than in non-tumor tissues (P < 0.05). Increased expression of alpha-taxilin protein in primary tumors was related to local invasion (P < 0.001), pathological vessel invasion (P < 0.001), and metastasis (P < 0.0001). Kaplan-Meier plots of survival for patients with low versus high alpha-taxilin expression revealed that high expression in tumor tissues was associated with shorter overall survival in all patients (P < 0.05) and with shorter disease-free survival in patients without metastasis (P < 0.01). These findings suggest that alpha-taxilin influences the metastatic and invasive potential of RCC.Intracellular vesicle trafficking is the principal transportation system in eukaryotic cells, and vesicle trafficking is thought to be involved in various processes related to cell proliferation. Abnormal proliferation is the hallmark of cancer. Recently, a protein named alpha (α)-taxilin was identified as a binding partner of the syntaxin family, which is involved in the coordination of intracellular vesicle trafficking (26). The taxilin family has at least three members-α-, beta (β)-, and gamma (γ)-taxilin-and α-taxilin possesses an extremely long coiled-coil region and interacts with syntaxin family members localized on the plasma membrane, but not with those localized on intracellular organelles (26, 28). There is evidence that the taxilin family is involved in the transfer of vesicles delivered to the plasma membrane (26, 28). However, the precise influence of the taxilin family on the functions of the syntaxin family remains to be fully elucidated, and the actual role of α-taxilin in intracellular vesicle trafficking is also unknown. In addition to providing information about the molecular mechanisms involved, examination of the physiological and pathophysiological functions of taxilin should improve our understanding about the role of this family of proteins. We recently reported that α-taxilin protein is significantly upregulated in proliferating neural stem cells during embryonic development in the rat (37). In addition, Oba-Shinjo et al. recently reported that

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Activation of the JNK–AP-1 signal transduction pathway is associated with pathogenesis and progression of human osteosarcomas

Cited by 99 publications

References 26 publications

Podoplanin Is Regulated by AP-1 and Promotes Platelet Aggregation and Cell Migration in Osteosarcoma

Podoplanin Is Regulated by AP-1 and Promotes Platelet Aggregation and Cell Migration in Osteosarcoma

Antimony-resistant but not antimony-sensitiveLeishmania donovaniup-regulates host IL-10 to overexpress multidrug-resistant protein 1

Increased alpha-taxilin protein expression is associated with the metastatic and invasive potential of renal cell cancer

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