Characterization of STAT3 activation and expression in canine and human osteosarcoma

Fossey, Stacey L.; Liao, Albert; McCleese, Jennifer; Bear, Misty D.; Lin, Jiayuh; Li, Pui-Kai; Kisseberth, William C.; London, Cheryl A.

doi:10.1186/1471-2407-9-81

Cited by 102 publications

(146 citation statements)

References 46 publications

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“…We also treated the human rhabodomyosarcoma cells with a low molecular weight compound STA-21 or block STAT3 signaling by dominant-negative STAT3 mutant, both of which induced rhabdomyosarcoma cell growth inhibition and apoptosis (37,47). Persistently activated STAT3 was also found in canine osteosarcoma (48). Our current study extended previous findings to show that blocking constitutive STAT3 activation in rhabodomyosarcoma cells inhibited cell growth and induced apoptosis through newly developed small molecule inhibitors and other JAK2/STAT3 inhibitors.…”

Section: Discussionsupporting

confidence: 76%

Two small molecule compounds, LLL12 and FLLL32, exhibit potent inhibitory activity on STAT3 in human rhabdomyosarcoma cells

Wei

Ball²,

Lin³

et al. 2010

Int J Oncol

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Abstract. Signal transducers and activators of transcription 3 (STAT3) signaling is persistently activated in many types of cancer cells, and represents a valid target for anticancer drug design. However, few reports have described the constitutive activation of STAT3 in human sarcoma cells. In this study, we demonstrate that the STAT3 signaling pathway is constitutively activated in human rhabodomyosarcoma cells (RH28, RH30, and RD2). We also investigated the inhibitory effects of two newly developed small molecules, LLL12 and FLLL32, on the STAT3 signaling pathway in human rhabodomyosarcoma cells. Both LLL12 and FLLL32 downregulated STAT3 constitutively and interleukin-6 (IL-6) stimulated phosphorylated STAT3 (p-STAT3). The inhibition of STAT3 via LLL12 and FLLL32 was confirmed by the inhibition of STAT3 DNA binding activity. The downstream targets of STAT3, cyclin D1, Bcl-xL, and survivin were also downregulated by LLL12 and FLLL 32 at both messenger RNA and protein levels. The potency of LLL12 and FLLL32 to inhibit proliferation/viability in human rhabodomyosarcoma cells (RH28, RH30, and RD2) was higher than that of the 5 previously reported Janus kinase 2 (JAK2)/ STAT3 inhibitors (LLL3, WP1066, Stattic, S3I-201, and AG490) and curcumin. Thus, in this study, we investigated the inhibitory effects of two STAT3 inhibitors, LLL12 and FLLL32, on the STAT3 signaling pathway in human rhabodomyosarcoma cells; we also demonstrated their higher potency in inhibiting proliferation on human rhabodomyosarcoma cells as compared to other five JAK2/STAT3 inhibitors and curcumin. IntroductionRhabdomyosarcoma, a highly malignant mesenchymal tumor, originating from immature striaed muscle, is the most common soft tissue sarcoma in children (1). Patients with rhabodomyosarcoma have a high relapse rate of 30% (1,2). Despite aggressive therapy, incorporating surgery, radiation therapy and dose-intensive chemotherapy, mortality rate of relapsing rhabodomyosarcoma is still 50-80% (2,3). Thus, development of higher potency and less toxicity anticancer drugs is pivotal to improve survival for patients with rhabdomyosarcoma.Signal transducers and activators of transcription 3 (STAT3) signaling is constitutively activated in various types of cancer cells, such as breast cancer, prostate cancer, leukemia and lymphomas (4). Activated STAT3 binds the promoters of the targeted genes to control cell growth and survival. Thus, inhibition of STAT3 signaling pathway seems to be an attractive strategy for anticancer drug design (5,6). For the past few years, several small molecules of the JAK2/STAT3 inhibitors, such as WP1066 (7-9), LLL3 (10) and AG490 (11-13), Stattic (14,15) and S3I-201 (16,17), have been reported with a wide range of antitumor effects. Although persistent activation of STAT3 has been detected in diverse cancer cell lines and tissue, only few reports have described elevated p-STAT3 in rhabdomyosarcoma.

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Section: Discussionsupporting

confidence: 76%

Two small molecule compounds, LLL12 and FLLL32, exhibit potent inhibitory activity on STAT3 in human rhabdomyosarcoma cells

Wei

Ball²,

Lin³

et al. 2010

Int J Oncol

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“…Other research groups have reported similar results when indirectly and directly inhibiting survivin in osteosarcoma. In one recent article, inhibition of STAT3 activity (which caused downregulation of survivin expression) in canine and human osteosarcoma decreased cell proliferation and viability and induced caspase-3/7-mediated apoptosis in treated cells (39). Another group inhibited survivin in HeLa cells and observed caspasedependent cell death as well as mitotic failure, resulting in multinucleated cells, up to 8 and 16N (40).…”

Section: Discussionmentioning

confidence: 99%

Expression and Function of Survivin in Canine Osteosarcoma

et al. 2012

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Osteosarcoma has a high mortality rate and remains in need of more effective therapeutic approaches. Survivin is an inhibitor of apoptosis family member protein that blocks apoptosis and drives proliferation in human cancer cells where it is commonly elevated. In this study, we illustrate the superiority of a canine osteosarcoma model as a translational tool for evaluating survivin-directed therapies, owing to the striking similarities in gross and microscopic appearance, biologic behavior, gene expression, and signaling pathway alterations. Elevated survivin expression in primary canine osteosarcoma tissue correlated with increased histologic grade and mitotic index and a decreased disease-free interval (DFI). Survivin attenuation in canine osteosarcoma cells inhibited cell-cycle progression, increased apoptosis, mitotic arrest, and chemosensitivity, and cooperated with chemotherapy to significantly improve in vivo tumor control. Our findings illustrate the utility of a canine system to more accurately model human osteosarcoma and strongly suggest that survivin-directed therapies might be highly effective in its treatment. Cancer Res; 72(1); 249-59. Ó2011 AACR.

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“…In breast cancer cells and epithelial cells, STAT3 may modulates MEK5 and HSP27 protein expression [7,8]. In addition, STAT3 signaling may regulate the expression of MMP [4,[9][10][11][12], VEGF [4,11,12], and Smad [13,14]. However, STAT3-regulated genes are still unclear in HCC, so in this study, we investigated the STAT3-regulated genes in HCC cells.…”

mentioning

confidence: 99%

“…For example, some studies suggest that STAT pathway plays an important role in cell-cycle progression and resistance to apoptosis through the regulation of cyclin A [1], E [1,2], D1 [1,3], XIAP [1,3], Survivin [1,4], and caspase [1,5]. In prostate cancer cells, the activation of STAT3 may affect the telomerase activity [6].…”

mentioning

confidence: 99%

Silencing STAT3 may inhibit cell growth through regulating signaling pathway, telomerase, cell cycle, apoptosis and angiogenesis in hepatocellular carcinoma: potential uses for gene therapy

Wang

Liu²,

B³

et al. 2011

neo

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The genesis and development of hepatocellular carcinoma (HCC) is related to the abnormity of signaling pathway, telomerase, cell cycle, apoptosis, angiogenesis, and others, in which STAT3 signaling pathway plays a key role. The HCC cell line HepG 2 was transfected with small interfering RNA (siRNA) directed against STAT3. After 72 h, cell growth and cycle were analysed by MTT and Flow cytometry. Then, the protein was extracted and the protein expression of STAT3, Smad3, p44/42, TERT, caspase-3, XIAP, Grp-78, HSP-27, MMP-2, MMP-9, VEGF-A, cyclin A, and cyclin E was detected by Western blot. After the transfection, HCC cell growth was inhibited during the 24-72 h time period and the cell cycle was arrested in G0/G1. STAT3 protein expression was inhibited at 72 h after the transfection. Interestingly, Smad3, p-caspase-3, p-p44/42, Grp78, cyclin A, and cyclin E protein expression was increased at 72 h, while TERT, caspase-3, XIAP, MMP-2, MMP-9, and VEGF-A protein expression decreased at 72 h. However, P44/42, and HSP27 protein expression showed no change following transfection. The results demonstrated that STAT3 signaling pathway may participate in HCC genesis and development through regulating the protein expression of other signaling pathway, telomerase, apoptosis, cell cycle and angiogenesis; thereby, blockade of the Stat3 pathway represents a potential strategy for future treatment.

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Characterization of STAT3 activation and expression in canine and human osteosarcoma

Cited by 102 publications

References 46 publications

Two small molecule compounds, LLL12 and FLLL32, exhibit potent inhibitory activity on STAT3 in human rhabdomyosarcoma cells

Two small molecule compounds, LLL12 and FLLL32, exhibit potent inhibitory activity on STAT3 in human rhabdomyosarcoma cells

Expression and Function of Survivin in Canine Osteosarcoma

Silencing STAT3 may inhibit cell growth through regulating signaling pathway, telomerase, cell cycle, apoptosis and angiogenesis in hepatocellular carcinoma: potential uses for gene therapy

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