Triptolide blocks the STAT3 signaling pathway through induction of protein tyrosine phosphatase SHP-1 in multiple myeloma cells

Kim, Ji‐Hun; Park, Byoungduck

doi:10.3892/ijmm.2017.3122

Cited by 17 publications

(9 citation statements)

References 52 publications

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“…TPL has potent immunosuppressant and anti-inflammatory activities, exhibiting broad pharmacological effects against inflammation, fibrosis, cancer, viral infection, oxidative stress, and osteoporosis (41,42). TPL is known to have both antiproliferative and proapoptotic effects on a range of cancers (43,44) and was previously reported to modulate the activity of many genes, including those involved in apoptosis and NF-B-mediated responses (42,45). RNA polymerase II was recently shown to be selectively targeted by TPL, although the mechanism by which TPL inhibits RNA polymerase II activity is yet to be fully elucidated (46).…”

Section: Human Norovirus Replication In Intestinal Epithelial Cells Amentioning

confidence: 99%

Norovirus Replication in Human Intestinal Epithelial Cells Is Restricted by the Interferon-Induced JAK/STAT Signaling Pathway and RNA Polymerase II-Mediated Transcriptional Responses

Hosmillo

Chaudhry

Nayak

et al. 2020

mBio

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Human noroviruses (HuNoV) are a leading cause of viral gastroenteritis worldwide and a significant cause of morbidity and mortality in all age groups. The recent finding that HuNoV can be propagated in B cells and mucosa-derived intestinal epithelial organoids (IEOs) has transformed our ability to dissect the life cycle of noroviruses. Using transcriptome sequencing (RNA-Seq) of HuNoV-infected intestinal epithelial cells (IECs), we have found that replication of HuNoV in IECs results in interferon (IFN)-induced transcriptional responses and that HuNoV replication in IECs is sensitive to IFN. This contrasts with previous studies that suggested that the innate immune response may play no role in the restriction of HuNoV replication in immortalized cells. We demonstrated that inhibition of Janus kinase 1 (JAK1)/JAK2 enhanced HuNoV replication in IECs. Surprisingly, targeted inhibition of cellular RNA polymerase II-mediated transcription was not detrimental to HuNoV replication but instead enhanced replication to a greater degree than blocking of JAK signaling directly. Furthermore, we demonstrated for the first time that IECs generated from genetically modified intestinal organoids, engineered to be deficient in the interferon response, were more permissive to HuNoV infection. Taking the results together, our work revealed that IFN-induced transcriptional responses restrict HuNoV replication in IECs and demonstrated that inhibition of these responses mediated by modifications of the culture conditions can greatly enhance the robustness of the norovirus culture system. IMPORTANCE Noroviruses are a major cause of gastroenteritis worldwide, and yet the challenges associated with their growth in culture have greatly hampered the development of therapeutic approaches and have limited our understanding of the cellular pathways that control infection. Here, we show that human intestinal epithelial cells, which represent the first point of entry of human noroviruses into the host, limit virus replication by induction of innate responses. Furthermore, we show that modulating the ability of intestinal epithelial cells to induce transcriptional responses to HuNoV infection can significantly enhance human norovirus replication in culture. Collectively, our findings provide new insights into the biological pathways that control norovirus infection but also identify mechanisms that enhance the robustness of norovirus culture.

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Section: Human Norovirus Replication In Intestinal Epithelial Cells Amentioning

confidence: 99%

Norovirus Replication in Human Intestinal Epithelial Cells Is Restricted by the Interferon-Induced JAK/STAT Signaling Pathway and RNA Polymerase II-Mediated Transcriptional Responses

Hosmillo

Chaudhry

Nayak

et al. 2020

mBio

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“…Initially, TPL has been demonstrated to cause global transcriptional inhibition via the largest subunit of RNA polymerase II (Zhao et al, 2012). Recently, TPL is believed to target specific transcription factors, such as Bcl-2, Bcl-xL, NF-kB, pRB, RNA polymerases (Wu et al, 2014;Zhang, Ho & Wong, 2018;Li et al, 2017;Guan et al, 2017;Kim & Park, 2017). In this study, we provide evidence that TPL inhibits β-tubulin and HSP90.…”

Section: Discussionmentioning

confidence: 63%

Discovery of potential targets of Triptolide through inverse docking in ovarian cancer cells

Wu¹,

Bao²,

Pan³

et al. 2020

PeerJ

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Triptolide (TPL) is proposed as an effective anticancer agent known for its anti-proliferation of a variety of cancer cells including ovarian cancer cells. Although some studies have been conducted, the mechanism by which TPL acts on ovarian cancer remains to be clearly described. Herein, systematic work based on bioinformatics was carried out to discover the potential targets of TPL in SKOV-3 cells. TPL induces the early apoptosis of SKOV-3 cells in a dose- and time-dependent manner with an IC50 = 40 ± 0.89 nM when cells are incubated for 48 h. Moreover, 20 nM TPL significantly promotes early apoptosis at a rate of 40.73%. Using a self-designed inverse molecular docking protocol, we fish the top 19 probable targets of TPL from the target library, which was built on 2,250 proteins extracted from the Protein Data Bank. The 2D-DIGE assay reveals that the expression of eight genes is affected by TPL. The results of western blotting and qRT-PCR assay suggest that 40 nM of TPL up-regulates the level of Annexin A5 (6.34 ± 0.07 fold) and ATP syn thase (4.08 ± 0.08 fold) and down-regulates the level of β-Tubulin (0.11 ± 0.12 fold) and HSP90 (0.21 ± 0.09 fold). More details of TPL affecting on Annexin A5 signaling pathway will be discovered in the future. Our results define some potential targets of TPL, with the hope that this agent could be used as therapy for the preclinical treatment of ovarian cancer.

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“…31 Recently, TPL is believed to target specific transcription factors, such as Bcl-2, Bcl-xL, NF-kB, pRB, RNA polymerases. [32][33][34][35][36] In this study, we provide evidence that TPL inhibits β-tubulin and HSP90. Several natural products including paclitaxel, colchicine, and vinca alkaloids have been proved to bind β-tubulin at a distinct binding site.…”

Section: Effects Of Tpl On the Expression Of Novel Proteinsmentioning

confidence: 57%

Peer Review #2 of "Discovery of potential targets of Triptolide through inverse docking in ovarian cancer cells (v0.1)"

2020

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Triptolide (TPL) is proposed as an effective anticancer agent known for its anti-proliferation of a variety of cancer cells including ovarian cancer cells. Although some studies have been conducted, the mechanism by which TPL acts on ovarian cancer remains to be clearly described. Herein, systematic work based on bioinformatics was carried out to discover the potential targets of TPL in SKOV-3 cells. TPL induces the early apoptosis of SKOV-3 cells in a dose-and time-dependent manner with an IC 50 =40±0.89 nM when cells are incubated for 48h. Moreover, 20 nM TPL significantly promotes early apoptosis at a rate of 40.73%. Using a self-designed inverse molecular docking protocol, we fish the top nineteen probable targets of TPL from the target library which are built on 2250 proteins extracted from the Protein Data Bank. The 2D-DIGE assay reveals that the expression of eight genes is affected by TPL. The results of western blotting and qRT-PCR assay suggest that 40 nM of TPL up-regulates the level of Annexin A 5 (6.34±0.07 fold) and ATP syn thase (4.08±0.08 fold), and down-regulates the level of β-Tubulin (0.11±0.12 fold) and HSP90 (0.21±0.09 fold). More details of TPL affecting on Annexin A5 signaling pathway will be discovered in the future. Our results define some potential targets of TPL, with the hope that this agent could be used as therapy for the preclinical treatment of ovarian cancer.

show abstract

Triptolide blocks the STAT3 signaling pathway through induction of protein tyrosine phosphatase SHP-1 in multiple myeloma cells

Cited by 17 publications

References 52 publications

Norovirus Replication in Human Intestinal Epithelial Cells Is Restricted by the Interferon-Induced JAK/STAT Signaling Pathway and RNA Polymerase II-Mediated Transcriptional Responses

Norovirus Replication in Human Intestinal Epithelial Cells Is Restricted by the Interferon-Induced JAK/STAT Signaling Pathway and RNA Polymerase II-Mediated Transcriptional Responses

Discovery of potential targets of Triptolide through inverse docking in ovarian cancer cells

Peer Review #2 of "Discovery of potential targets of Triptolide through inverse docking in ovarian cancer cells (v0.1)"

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