Tyrosine kinase inhibitor tyrphostin AG490 triggers both apoptosis and autophagy by reducing HSF1 and Mcl-1 in PEL cells

Granato, Marisa; Chiozzi, Barbara; Filardi, Maria Rosaria; Lotti, Lavinia Vittoria; Renzo, Livia Di; Faggioni, Alberto; Cirone, Mara

doi:10.1016/j.canlet.2015.07.006

Cited by 32 publications

(30 citation statements)

References 33 publications

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“…Overexpression of LANA1 enhanced STAT3 activity, and inhibition of LANA1 expression decreased the STAT3dependent transcription (20). Consistent with the effects of AG490, a tyrosine kinase inhibitor, on STAT3 activity in PEL cells (42), triptolide reduced STAT3 activity in PEL cells. In addition, IL-6 is a pivotal cytokine contributing to cell survival.…”

Section: Discussionsupporting

confidence: 68%

Triptolide decreases expression of latency-associated nuclear antigen 1 and reduces viral titers in Kaposi's sarcoma-associated and herpesvirus-related primary effusion lymphoma cells

Long

Guo

Zhou

et al. 2016

International Journal of Oncology

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Kaposi's sarcoma-associated herpesvirus (KSHV) can establish a life-long persistence in the host after primary infection and is associated with certain malignancies, which are resistant to conventional chemotherapeutic agents with a poor prognosis. Latency-associated nuclear antigen 1 (LANA1) encoded by KSHV is essential for segregation, replication and maintenance of viral genome. In addition, LANA1 upregulates the transcriptional activity of signal transducer and activator of transcription 3 (STAT3), which plays an important role in promoting survival of KSHV-associated primary effusion lymphoma (PEL) cells. Furthermore, LANA1 mediates transcriptional modulation of KSHV and host genome in host cells. In the present study, the antitumor effect of triptolide was assessed. CCK-8 assays were performed to demonstrate that the proliferations of PEL cells were efficiently inhibited by triptolide in a dose- and time-dependent manner. Flow cytometric results indicated that triptolide induced cell cycle arrest and apoptosis. Western blot results suggested that triptolide downregulated LANA1 expression and reduced half-life of LANA1 in the KSHV-infected malignant cells. Viral titer experiments indicated that triptolide treatment impaired the number of viral DNA copies and the production of virions in BCBL-1 cells. Triptolide also suppressed STAT3 activity and inhibited secretion of IL-6 in PEL cells. In a mouse xenograft model of primary effusion lymphoma by BCBL-1 cells, triptolide treatment significantly inhibited ascites formation and diffused organ infiltration. These results indicate that triptolide impairs the expression of LANA1 and shows antitumor activity against PEL in vitro and in vivo. Triptolide may be a potential agent for treatment of PEL.

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Section: Discussionsupporting

confidence: 68%

Triptolide decreases expression of latency-associated nuclear antigen 1 and reduces viral titers in Kaposi's sarcoma-associated and herpesvirus-related primary effusion lymphoma cells

Long

Guo

Zhou

et al. 2016

International Journal of Oncology

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“…Intracellular ROS are important to maintain cancer cell survival through the activation of oncogenic pathways such as STAT3 [ 33 ] that is strongly involved in PEL cell survival [ 11 – 13 ]. Therefore we evaluated whether apigenin could modify STAT3 activation and found that it strongly reduced STAT3 phosphorylation in both BC3 and BCBL1 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…PEL is a Kaposi Sarcoma Associated Herpesvirus (KSHV)-associated malignant B cell lymphoma highly refractory to conventional chemotherapies [ 8 ], but displaying a good susceptibility to treatment with natural products such as capsaicin [ 9 , 10 ]. These molecules share the characteristic to concomitantly inhibit multiple oncogenic pathways such as AKT and STAT3, strongly involved in PEL cell survival [ 11 – 13 ]. The latter indeed positively regulates the expression of pro-survival molecules such as survivin, cyclinD1 and c-myc [ 14 , 15 ] or anti-apoptotic proteins such as c-FLIP [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Apigenin, by activating p53 and inhibiting STAT3, modulates the balance between pro-apoptotic and pro-survival pathways to induce PEL cell death

Granato

Montani

Santarelli

et al. 2017

J Exp Clin Cancer Res

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BackgroundApigenin is a flavonoid widely distributed in plant kingdom that exerts cytotoxic effects against a variety of solid and haematological cancers. In this study, we investigated the effect of apigenin against primary effusion lymphoma (PEL), a KSHV-associated B cell lymphoma characterized by a very aggressive behavior, displaying constitutive activation of STAT3 as well as of other oncogenic pathways and harboring wtp53.MethodsCell death was assessed by trypan blue exclusion assay, FACS analysis as well as by biochemical studies. The latter were also utilized to detect the occurrence of autophagy and the molecular mechanisms leading to the activation of both processes by apigenin. FACS analysis was used to measure the intracellular ROS utilizing DCFDA.ResultsWe show that apigenin induced PEL cell death and autophagy along with reduction of intracellular ROS. Mechanistically, apigenin activated p53 that induced catalase, a ROS scavenger enzyme, and inhibited STAT3, the most important pro-survival pathway in PEL, as assessed by p53 silencing. On the other hand, STAT3 inhibition by apigenin resulted in p53 activation, since STAT3 negatively influences p53 activity, highlighting a regulatory loop between these two pathways that modulates PEL cell death/survival.ConclusionThe findings of this study demonstrate that apigenin may modulate pro-apoptotic and pro-survival pathways representing a valid therapeutic strategy against PEL.

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“…Interestingly, a previous study proved that the JAK2/STAT3 signaling pathway can regulate HSP70 expression to affect the development of diseases. Specifically, Granato M et al found that blocking JAK2/STAT3 could reduce the expression of HSP70, thereby down-regulating Mcl-1 expression and inducing apoptosis and the autophagy of PEL cells [ 18 ]. By treating BL Raji cells with HSP70 siRNA and recombinant Human JAK2, we also found that the proliferation, cell cycle distribution, and apoptosis of Raji cells did not significantly differ from the cells in the Blank group, further suggesting that the JAK2/STAT3 pathway may affect the pathogenesis and progression of BL by modulating HSP70 expression.…”

Section: Discussionmentioning

confidence: 99%

“…A previous study reported that the over-expression of HSP70 was closely associated with apoptotic resistance (AR) in pancreatic cancer, which is involved in abnormal JAK2/STAT3 pathway signaling [ 17 ]. Moreover, inhibition of the JAK2/STAT3 pathway could reduce the expression of HSP70 and then induce apoptosis and autophagy in primary effusion lymphoma (PEL) cells [ 18 ]. To the best of our knowledge, the JAK/STAT pathway is abnormally expressed in many lymphomas, which can lead to the survival/proliferation of cells and tumor immune evasion [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of JAK2/STAT3 Signaling Pathway Suppresses Proliferation of Burkitt’s Lymphoma Raji Cells via Cell Cycle Progression, Apoptosis, and Oxidative Stress by Modulating HSP70

Chen

Liu

et al. 2018

Med Sci Monit

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BackgroundThe aim of this study was to investigate the effect of the JAK2/STAT3 pathway on the proliferation, cell cycle distribution, apoptosis, and oxidative stress of Raji cells via regulating HSP70 expression.Material/MethodsRaji cells were divided into Blank, HSP70 siRNA, NC siRNA, AG490 (a JAK2/STAT3 signaling pathway inhibitor), and HSP70 siRNA + rh JAK2 (recombinant human JAK2) groups. HSP70 expression was detected by quantitative real-time reverse transcription-PCR (qRT-PCR); the expression levels of HSP70 and JAK2/STAT3 pathway-related proteins were evaluated by Western blotting; cell proliferation was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays; cell cycle distribution was observed by flow cytometry; cell apoptosis was tested by Annexin V-FITC/PI and Hoechst 33342/PI staining; reactive oxygen species (ROS) production was measured by dichloro-dihydro-fluorescein diacetate (DCFH-DA) assays; and MDA content and SOD and GSH-Px activities were determined using detection kits.ResultsAG490 obviously down-regulated HSP70 expression, inhibited proliferation, induced cell cycle arrest at the G0/G1 phase, and promoted apoptosis in Raji cells; these effects were similar to the effects of HSP70 siRNA. Furthermore, ROS production and MDA content were increased in Raji cells treated with HSP70 siRNA or AG490, while SOD and GSH-Px activities were reduced. Raji cells in the HSP70 siRNA + rh JAK2 group did not significantly differ from those in the Blank group in regards to proliferation, cell cycle, apoptosis, and oxidative stress.ConclusionsBlocking the JAK2/STAT3 signaling pathway may inhibit proliferation, induce cell cycle arrest, and promote oxidative stress and apoptosis in Raji cells via the down-regulation of HSP70.

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Tyrosine kinase inhibitor tyrphostin AG490 triggers both apoptosis and autophagy by reducing HSF1 and Mcl-1 in PEL cells

Cited by 32 publications

References 33 publications

Triptolide decreases expression of latency-associated nuclear antigen 1 and reduces viral titers in Kaposi's sarcoma-associated and herpesvirus-related primary effusion lymphoma cells

Triptolide decreases expression of latency-associated nuclear antigen 1 and reduces viral titers in Kaposi's sarcoma-associated and herpesvirus-related primary effusion lymphoma cells

Apigenin, by activating p53 and inhibiting STAT3, modulates the balance between pro-apoptotic and pro-survival pathways to induce PEL cell death

Inhibition of JAK2/STAT3 Signaling Pathway Suppresses Proliferation of Burkitt’s Lymphoma Raji Cells via Cell Cycle Progression, Apoptosis, and Oxidative Stress by Modulating HSP70

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