Requirement of p38 MAPK for a cell-death pathway triggered by vorinostat in MDA-MB-231 human breast cancer cells

Uehara, Norihisa; Kanematsu, Sayaka; Miki, Hisanori; Yoshizawa, Katsuhiko; Tsubura, Airo

doi:10.1016/j.canlet.2011.07.032

Cited by 31 publications

(25 citation statements)

References 42 publications

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“…p38a activity has been demonstrated to promote TNBC oncogenesis via increased invasion, inflammation, and angiogenesis (55). The role of p38a in breast cancers has been studied in depth and very recently proposed as a therapeutic target in TNBC (56,57). ER-negative and mutant-p53 cell lines (which comprise the majority of TNBCs) were observed to be more sensitive to small-molecule inhibition of p38a than ER-positive and wt-p53 cell lines (58).…”

Section: Discussionmentioning

confidence: 99%

UM-164: A Potent c-Src/p38 Kinase Inhibitor with In Vivo Activity against Triple-Negative Breast Cancer

Gilani

Phadke

Bao

et al. 2016

Clinical Cancer Research

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Purpose: c-Src has been shown to play a pivotal role in breast cancer progression, metastasis, and angiogenesis. In the clinic, however, the limited efficacy and high toxicity of existing c-Src inhibitors have tempered the enthusiasm for targeting c-Src. We developed a novel c-Src inhibitor (UM-164) that specifically binds the DFG-out inactive conformation of its target kinases. We hypothesized that binding the inactive kinase conformation would lead to improved pharmacologic outcomes by altering the noncatalytic functions of the targeted kinases.Experimental Design: We have analyzed the anti-triple-negative breast cancer (TNBC) activity of UM-164 in a comprehensive manner that includes in vitro cell proliferation, migration, and invasion assays (including a novel patient-derived xenograft cell line, VARI-068), along with in vivo TNBC xenografts. Results:We demonstrate that UM-164 binds the inactive kinase conformation of c-Src. Kinome-wide profiling of UM-164 identified that Src and p38 kinase families were potently inhibited by UM-164. We further demonstrate that dual c-Src/p38 inhibition is superior to mono-inhibition of c-Src or p38 alone. We demonstrate that UM-164 alters the cell localization of c-Src in TNBC cells. In xenograft models of TNBC, UM-164 resulted in a significant decrease of tumor growth compared with controls, with limited in vivo toxicity.Conclusions: In contrast with c-Src kinase inhibitors used in the clinic (1, 2), we demonstrate in vivo efficacy in xenograft models of TNBC. Our results suggest that the dual activity drug UM-164 is a promising lead compound for developing the first targeted therapeutic strategy against TNBC.

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Section: Discussionmentioning

confidence: 99%

UM-164: A Potent c-Src/p38 Kinase Inhibitor with In Vivo Activity against Triple-Negative Breast Cancer

Gilani

Phadke

Bao

et al. 2016

Clinical Cancer Research

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“…The mitogen-activated protein kinases (MAPK) pathways, i.e., ERK, SAPK/JNK and p38 MAPK, are actively involved in drug-induced cell apoptosis of numerous cancer cells (46). Activation of JNK and p38 MAPK pathways results in enhanced apoptosis induced by berberine in human hepatoma and colon carcinoma cells (34,35).…”

Section: Discussionmentioning

confidence: 99%

“…Activation of JNK and p38 MAPK pathways results in enhanced apoptosis induced by berberine in human hepatoma and colon carcinoma cells (34,35). When the MAPKs are inhibited, the apoptosis and caspase-3 cleavage in tumor cells are abrogated (46)(47)(48). Moreover, inhibitors of MAPKs slightly increase cell viability in MDA-MB-231 cells (49).…”

Section: Discussionmentioning

confidence: 99%

Berberine hydrochloride IL-8 dependently inhibits invasion and IL-8-independently promotes cell apoptosis in MDA-MB-231 cells

Zhao

Shi

et al. 2014

Oncology Reports

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Abstract. Breast cancer, the leading cause of cancer-related mortality worldwide in females, has high metastastic and recurrence rates. The aim of the present study was to evaluate the anti-metastatic and anticancer in situ effect of berberine hydrochloride (BER) in MDA-MB-231 cells. BER dose-dependently inhibited proliferation and the IL-8 secretion of MDA-MB-231 cells. Additional experiments revealed that the inactivation of PI3K, JAK2, NF-κB and AP-1 by BER contributed to the decreased IL-8 secretion. BER abrogated cell invasion induced by IL-8 accompanied with the downregulation of the gene expression of MMP-2, EGF, E-cadherin, bFGF and fibronectin.In addition, BER reduced cell motility but induced G2/M arrest and cell apoptosis in an IL-8-independent manner. BER modulated multiple signaling pathway molecules involved in the regulation of cell apoptosis, including activation of p38 MAPK and JNK and deactivation of JAK2, p85 PI3K, Akt and NF-κB. The enhanced cell apoptosis induced by BER was eliminated by inhibitors of p38 MAPK and JNK but was strengthened by activator of p38 MAPK. Thus, BER inhibited cell metastasis partly through the IL-8 mediated pathway while it induced G2/M arrest and promoted cell apoptosis through the IL-8 independent pathway. Apoptosis induced by BER was mediated by crosstalks of various pathways including activation of p38 MAPK and JNK pathways and inactivation of JAK2/ PI3K/NF-κB/AP-1 pathways. The results suggested that BER may be an efficient and safe drug candidate for treating highly metastatic breast cancer.

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“…As shown in Fig. 1, the effect of vorinostat on the blockade of BrdU incorporation peaked at 24 h (~95% in both cell lines), and it persisted until 72 h (~88% in MDA-MB-231 and ~84% in MCF-7), which was correlated with the acetylation status of histone H3 and growth inhibition (15).…”

Section: Resultsmentioning

confidence: 66%

“…Our data imply that not only the transcriptional activation of p21, but also the enhanced protein stability of p27 and p21 through the modulation of Skp2 and Cks1, may contribute to the vorinostat-induced growth arrest of human breast cancer cells. were maintained as previously described (15). Vorinostat (suberoylanilide-hydroxamic acid) was obtained from Selleck (Houston, TX).…”

Section: Introductionmentioning

confidence: 99%

Vorinostat enhances protein stability of p27 and p21 through negative regulation of Skp2 and Cks1 in human breast cancer cells

2012

Self Cite

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Abstract. Vorinostat is a histone deacetylase inhibitor that blocks cancer cell proliferation through the regulation of cyclin-dependent kinase inhibitors. We, herein, examined the involvement of S-phase kinase-associated protein 2 (Skp2) and cyclin-dependent kinase subunit 1 (Cks1), the components of the SCF Skp2-Cks1 (Skp1/Cul1/F-box protein) ubiquitin ligase complex, in the regulation of p27 and p21 during vorinostatinduced growth arrest of MDA-MB-231 and MCF-7 human breast cancer cells. Vorinostat significantly reduced BrdU incorporation in MDA-MB-231 and MCF-7 cells, which was associated with increased p27 and p21 protein levels without concomitant induction of p27 mRNA. Vorinostatinduced accumulation of p27 and p21 proteins was inversely correlated with the mRNA and protein levels of Skp2 and Cks1. Cycloheximide chase analysis revealed that vorinostat increased the half-life of p27 and p21 proteins. The accumulation of p27 and p21 proteins was attenuated by forced expression of Skp2 and Cks1, which conferred resistance to the vorinostat-induced S-phase reduction. These results suggest that vorinostat-induced growth arrest may be in part due to the enhanced protein stability of p27 and p21 through the downregulation of Skp2 and Cks1. IntroductionCell cycle progression is tightly controlled by the activities of cyclin-dependent kinases (CDKs) and CDK inhibitors (CKIs), such as p27 and p21 (1). Timely degradation of these proteins is required for proper cell-cycle progression. S-phase kinase associated protein 2 (Skp2) and cyclin-dependent kinase subunit 1 (Cks1) are the subunits of the SCF (Skp1/Cul1/F-box protein) ubiquitin ligase complex that are responsible for S-phase entry through the ubiquitination of p27 and p21, which is followed by their degradation by the proteasome pathway (2). Many cancer cells exhibit abnormal proliferation that is attributed to aberrant cell cycle progression. Numerous studies have reported the loss of p27 in a wide variety of malignancies including breast cancer (3,4). The loss of p27 was due to accelerated degradation by the ubiquitin-proteasome pathway, rather than transcriptional repression. In fact, overexpression of Skp2 and/or Cks1 has been found in breast cancer tissues and is an independent prognostic marker for disease-free and overall survival and is associated with aggressiveness (5-9). In cell culture, higher expression levels of Skp2 were found in estrogen receptor (ER)/Her2-negative aggressive breast cancer cells, such as MDA-MB-231, as compared to MCF-7 ER-positive breast cancer cells (6,7).Vorinostat is a potent histone deacetylase inhibitor (HDACi) that exerts antitumor effects by inducing differentiation, growth arrest and/or apoptosis through acetylation modification of histones and/or non-histone proteins (10). Vorinostat induces cell-cycle arrest at the G1 or the G2/M boundary in a cell-type dependent and/or dose-related fashion (11). The transactivation of CDKN1A, which encodes p21, is commonly observed after HDACi treatment (12). In addition, induction ...

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Requirement of p38 MAPK for a cell-death pathway triggered by vorinostat in MDA-MB-231 human breast cancer cells

Cited by 31 publications

References 42 publications

UM-164: A Potent c-Src/p38 Kinase Inhibitor with In Vivo Activity against Triple-Negative Breast Cancer

UM-164: A Potent c-Src/p38 Kinase Inhibitor with In Vivo Activity against Triple-Negative Breast Cancer

Berberine hydrochloride IL-8 dependently inhibits invasion and IL-8-independently promotes cell apoptosis in MDA-MB-231 cells

Vorinostat enhances protein stability of p27 and p21 through negative regulation of Skp2 and Cks1 in human breast cancer cells

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