JAK2/STAT3 targeted therapy suppresses tumor invasion via disruption of the EGFRvIII/JAK2/STAT3 axis and associated focal adhesion in EGFRvIII-expressing glioblastoma

Zheng, Qi-Fan; Han, Lei; Dong, Yucui; Tian, Jing; Huang, Wei; Liu, Zhaoyu; Jia, Xiuzhi; Jiang, Tao; Zhang, Jianning; Li, Xia; Kang, Chunsheng; Ren, Huan

doi:10.1093/neuonc/nou046

Cited by 79 publications

(75 citation statements)

References 45 publications

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“…3a, b). In addition, CPT inhibited phosphorylation of EGFR (Epidermal growth factor receptor), an upstream regulator of Stat3 activation [23], in HCT116 and SW480 cell lines (Fig. 4a, b); however, EGFR inactivation was only observed at higher concentrations in both the HCT116 and SW480 cell lines.…”

Section: Cpt Inhibits Stat3 Activation In Colorectal Cancer Cellsmentioning

confidence: 94%

Cryptotanshinone, a Stat3 inhibitor, suppresses colorectal cancer proliferation and growth in vitro

Saud

Young

et al. 2015

Mol Cell Biochem

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Cryptotanshinone (CPT) is a natural compound extracted from herbal medicine that has been previously shown to possess antitumor properties in various types of human cancer cells. In the present study, we examined the potential role of CPT in the treatment of colorectal cancer. Using SW480, HCT116, and LOVO colorectal cancer cell lines, the effects of CPT on cell viability, apoptosis, and tumorigenicity were evaluated. The results showed that CPT significantly inhibited the growth and viability of SW480, HCT116, and LOVO cell lines by inducing apoptosis and prevented anchorage dependent growth on agar. In addition, CPT inhibited the activation of Signal transducer and activator of transcription 3 (Stat3) pathways in colorectal cancer cells. Stat3 is a transcription factor that mediates the expression of various genes associated with many cellular processes, such as inflammation and cell growth, and has been shown to promote several cancer types, including colorectal cancer. These findings indicate that CPT may be a potential candidate for the treatment and prevention of colorectal cancer in part by inhibiting the activation of Stat3.

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Section: Cpt Inhibits Stat3 Activation In Colorectal Cancer Cellsmentioning

confidence: 94%

Cryptotanshinone, a Stat3 inhibitor, suppresses colorectal cancer proliferation and growth in vitro

Saud

Young

et al. 2015

Mol Cell Biochem

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“…A particular mutation of this receptor, EGFR variant III (EGFRvIII), is often coexpressed along with EGFR amplification in GBM. EGFRvIII and FAK interact as part of a complex to mediate EGFRvIIImediated MAPK activation (27). Given the demonstrated role of MDA-9/Syntenin in enhancing downstream signaling of the FAKSrc complex in melanoma (13), we determined whether PDZ1i could inhibit EGFRvIII signaling in GBM.…”

Section: Epha2 Signaling Postradiation It Can Be Considered a Valuabmentioning

confidence: 99%

Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin

Kegelman

Das

et al. 2016

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

130

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Glioblastoma multiforme (GBM) is an intractable tumor despite therapeutic advances, principally because of its invasive properties. Radiation is a staple in therapeutic regimens, although cells surviving radiation can become more aggressive and invasive. Subtraction hybridization identified melanoma differentiation-associated gene 9 [MDA-9/Syntenin; syndecan-binding protein (SDCBP)] as a differentially regulated gene associated with aggressive cancer phenotypes in melanoma. MDA-9/Syntenin, a highly conserved double-PDZ domain-containing scaffolding protein, is robustly expressed in human-derived GBM cell lines and patient samples, with expression increasing with tumor grade and correlating with shorter survival times and poorer response to radiotherapy. Knockdown of MDA-9/Syntenin sensitizes GBM cells to radiation, reducing postradiation invasion gains. Radiation induces Src and EGFRvIII signaling, which is abrogated through MDA-9/Syntenin down-regulation. A specific inhibitor of MDA-9/Syntenin activity, PDZ1i (113B7), identified through NMR-guided fragment-based drug design, inhibited MDA-9/Syntenin binding to EGFRvIII, which increased following radiation. Both genetic (shmda-9) and pharmacological (PDZ1i) targeting of MDA-9/Syntenin reduced invasion gains in GBM cells following radiation. Although not affecting normal astrocyte survival when combined with radiation, PDZ1i radiosensitized GBM cells. PDZ1i inhibited crucial GBM signaling involving FAK and mutant EGFR, EGFRvIII, and abrogated gains in secreted proteases, MMP-2 and MMP-9, following radiation. In an in vivo glioma model, PDZ1i resulted in smaller, less invasive tumors and enhanced survival. When combined with radiation, survival gains exceeded radiotherapy alone. MDA-9/Syntenin (SDCBP) provides a direct target for therapy of aggressive cancers such as GBM, and defined small-molecule inhibitors such as PDZ1i hold promise to advance targeted brain cancer therapy.

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“…Despite efforts for improvement, including development of targeted therapies [9], prognosis remains dismal, with a median survival of~14 months. Most of the difficulties in treating glioblastomas are a consequence of its localization behind the blood-brain barrier (BBB), thus limiting the bioavailability of chemotherapies.…”

Section: Introductionmentioning

confidence: 99%

Autophagy inhibition improves the efficacy of curcumin/temozolomide combination therapy in glioblastomas

et al. 2015

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Glioblastoma is a devastating primary brain tumor resistant to conventional therapies. In this study, we tested the efficacy of combining temozolomide with curcumin, a phytochemical known to inhibit glioblastoma growth, and investigated the mechanisms involved. The data showed that synergy between curcumin and temozolomide was not achieved due to redundant mechanisms that lead to activating protective autophagy both in vitro and in vivo. Autophagy preceded apoptosis, and blocking this response with autophagy inhibitors (3-methyl-adenine, ATG7 siRNA and chloroquine) rendered cells susceptible to temozolomide and curcumin alone or combinations by increasing apoptosis. While curcumin inhibited STAT3, NFκB and PI3K/Akt to affect survival, temozolomide-induced autophagy relied on the DNA damage response and repair components ATM and MSH6, as well as p38 and JNK1/2. However, the most interesting observation was that both temozolomide and curcumin required ERK1/2 to induce autophagy. Blocking this ERK1/2-mediated temozolomide and curcumin induced autophagy with resveratrol, a blood-brain barrier permeable drug, improved temozolomide/curcumin efficacy in brain-implanted tumors. Overall, the data presented demonstrate that autophagy impairs the efficacy of temozolomide/curcumin, and inhibiting this phenomenon could provide novel opportunities to improve brain tumor treatment.

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JAK2/STAT3 targeted therapy suppresses tumor invasion via disruption of the EGFRvIII/JAK2/STAT3 axis and associated focal adhesion in EGFRvIII-expressing glioblastoma

Cited by 79 publications

References 45 publications

Cryptotanshinone, a Stat3 inhibitor, suppresses colorectal cancer proliferation and growth in vitro

Cryptotanshinone, a Stat3 inhibitor, suppresses colorectal cancer proliferation and growth in vitro

Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin

Autophagy inhibition improves the efficacy of curcumin/temozolomide combination therapy in glioblastomas

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