Lapatinib inhibits CIP2A/PP2A/p-Akt signaling and induces apoptosis in triple negative breast cancer cells

Liu, Chun Yu; Hu, Ming; Hsu, Chia-Jung; Huang, Chun Yao; Wang, Duen Shian; Tsai, Wen Chun; Chen, Yi Ting; Lee, Chia-Han; Chu, Pei Yi; Hsu, Chia Chi; Chen, Ming-Huang; Shiau, Chung Wai; Tseng, Ling Ming; Chen, Kuen Feng

doi:10.18632/oncotarget.7035

Cited by 44 publications

(26 citation statements)

References 61 publications

(75 reference statements)

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“…indicates that the JQ1 resistance developed by TNBC cell lines may be based on epigenetic mechanisms of adaptation, specifically, the gain of BRD4-targeted super-enhancers accompanied by increased levels of phosphorylated BRD4 due to a reduced PP2A phosphatase activity [22]. This fact supports the OTX015/everolimus approach since this enzyme is also an Akt pathway inhibitor [38]. However, further studies are required to fully understand the role of OTX015 and mTOR inhibitors in TNBC, given some of our seemingly inconsistent results; OTX015 treatment induced down-regulation of c-MYC expression in only MDA-MB-468 cells, where the combination of OTX015 with everolimus resulted in an antagonistic interaction.…”

Section: Discussionmentioning

confidence: 97%

The bromodomain inhibitor OTX015 (MK-8628) exerts anti-tumor activity in triple-negative breast cancer models as single agent and in combination with everolimus

Vázquez

Riveiro²,

Astorgues‐Xerri³

et al. 2016

Oncotarget

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Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subgroup of breast tumors clinically defined by the lack of estrogen, progesterone and HER2 receptors, limiting the use of the targeted therapies employed in other breast malignancies. Recent evidence indicates that c-MYC is a key driver of TNBC. The BET-bromodomain inhibitor OTX015 (MK-8628) has potent antiproliferative activity accompanied by c-MYC down-regulation in several tumor types, and has demonstrated synergism with the mTOR inhibitor everolimus in different models. The aim of this study was to evaluate the anti-tumor activity of OTX015 as single agent and in combination with everolimus in TNBC models. OTX015 was assayed in three human TNBC-derived cell lines, HCC1937, MDA-MB-231 and MDA-MB-468, all showing antiproliferative activity after 72 h (GI50 = 75–650 nM). This was accompanied by cell cycle arrest and decreased expression of cancer stem cells markers. However, c-MYC protein and mRNA levels were only down-regulated in MDA-MB-468 cells. Gene set enrichment analysis showed up-regulation of genes involved in epigenetic control of transcription, chromatin and the cell cycle, and down-regulation of stemness-related genes. In vitro, combination with everolimus was additive in HCC1937 and MDA-MB-231 cells, but antagonistic in MDA-MB-468 cells. In MDA-MB-231 murine xenografts, tumor mass was significantly (p < 0.05) reduced by OTX015 with respect to vehicle-treated animals (best T/C = 40.7%). Although everolimus alone was not active, the combination was more effective than OTX015 alone (best T/C = 20.7%). This work supports current clinical trials with OTX015 in TNBC (NCT02259114).

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Section: Discussionmentioning

confidence: 97%

The bromodomain inhibitor OTX015 (MK-8628) exerts anti-tumor activity in triple-negative breast cancer models as single agent and in combination with everolimus

Vázquez

Riveiro²,

Astorgues‐Xerri³

et al. 2016

Oncotarget

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“…CIP2A is recognized as a “druggable” target, and compounds including celastrol, ethoxysanguinarine, and rabdocoetsin B inhibit CIP2A and induce apoptosis of lung cancer cells. CIP2A is targeted by some kinase inhibitors and proteasome inhibitor to exert anti‐cancer activity. Therefore, identifying novel CIP2A inhibitors may provide optimal drug candidates for clinical testing.…”

Section: Introductionmentioning

confidence: 99%

The red wine component ellagic acid induces autophagy and exhibits anti‐lung cancer activity in vitro and in vivo

Duan

Zhan

Wang

et al. 2018

J Cellular Molecular Medi

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Red wine consists of a large amount of compounds such as resveratrol, which exhibits chemopreventive and therapeutic effects against several types of cancers by targeting cancer driver molecules. In this study, we tested the anti‐lung cancer activity of 11 red wine components and reported that a natural polyphenol compound ellagic acid (EA) inhibited lung cancer cell proliferation at an efficacy approximately equal to that of resveratrol. EA markedly increased the expression of the autophagosomal marker LC3‐II as well as inactivation of the mechanistic target of rapamycin signalling pathway. EA elevated autophagy‐associated cell death by down‐regulating the expression of cancerous inhibitor of protein phosphatase 2A (CIP2A), and CIP2A overexpression attenuated EA‐induced autophagy of lung cancer cells. Treating tumour‐bearing mice with EA resulted in significant inhibition of tumour growth with suppression of CIP2A levels and increased autophagy. In addition, EA potentiated the inhibitory effects of the natural compound celastrol on lung cancer cells in vitro and in vivo by enhancing autophagy and down‐regulating CIP2A. These findings indicate that EA may be a promising chemotherapeutic agent for lung cancer, and that the combination of EA and celastrol may have applicability for the treatment of this disease.

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“…The loss of activity of PP2A is frequently found in human breast, lung, colon, and skin cancers, and reactivating PP2A has been demonstrated to inhibit breast cancer and hepatocellular carcinoma . Therefore, the reactivation of PP2A activity through the inhibition of CIP2A is an attractive therapeutic strategy for cancer therapy …”

Section: Introductionmentioning

confidence: 99%

Cucurbitacin B induces inhibitory effects via CIP2A/PP2A/Akt pathway in glioblastoma multiforme

Qin

et al. 2018

Molecular Carcinogenesis

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Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a human oncoprotein that is overexpressed in multiple types of tumors and promotes the proliferation and transformation of cancer cells. However, whether CIP2A can be a new drug target for human glioblastoma multiforme (GBM) is largely unclear. In the present study, we demonstrated that the overexpression of CIP2A promotes invasive behavior in GBM, and a natural compound, cucurbitacin B (CuB), shows an anti-proliferative and anti-invasion effect in GBM cell lines. CuB effectively induces apoptosis, downregulates CIP2A expression and its downstream signaling molecule, phospho-Akt, and upregulates protein phosphatase 2A (PP2A) activity. Overexpression of CIP2A reduced CuB-inhibited growth and invasion in GBM cells. Silencing CIP2A enhanced CuB-induced invasion inhibition and apoptosis in GBM. CuB combined with cisplatin synergistically inhibited GBM cells. CuB also inhibited tumor growth in murine models. Western blot results further revealed that CuB downregulates CIP2A, and phospho-Akt in vivo. In summary, inhibition of CIP2A determines the effects of CuB-induced invasive behavior inhibition and apoptosis in GBM cells. These characteristics render CuB as a promising candidate drug for further development and for designing new effective CIP2A inhibitors.

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Lapatinib inhibits CIP2A/PP2A/p-Akt signaling and induces apoptosis in triple negative breast cancer cells

Cited by 44 publications

References 61 publications

The bromodomain inhibitor OTX015 (MK-8628) exerts anti-tumor activity in triple-negative breast cancer models as single agent and in combination with everolimus

The bromodomain inhibitor OTX015 (MK-8628) exerts anti-tumor activity in triple-negative breast cancer models as single agent and in combination with everolimus

The red wine component ellagic acid induces autophagy and exhibits anti‐lung cancer activity in vitro and in vivo

Cucurbitacin B induces inhibitory effects via CIP2A/PP2A/Akt pathway in glioblastoma multiforme

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