KU004 induces G1 cell cycle arrest in human breast cancer SKBR-3 cells by modulating PI3K/Akt pathway

Fu, Jing; Tian, Chongchong; Xing, Mengtao; Wang, Xinzhi; Guo, Hongli; Sun, Lixin; Sun, Li; Jiang, Zhijun; Zhang, Luyong

doi:10.1016/j.biopha.2014.05.006

Cited by 8 publications

(6 citation statements)

References 23 publications

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“…HER-2 is an oncogene in human carcinoma, and a number studies have demonstrated that it is significantly upregulated in several types of human malignancy, with studies indicating that HER-2 is important in tumor cell proliferation, invasion and apoptosis (22,23). Our previous study demonstrated that overexpression of HER-2 in patients with meningioma was associated with poor prognosis (24).…”

Section: Discussionmentioning

confidence: 95%

Role of HER-2 activity in the regulation of malignant meningioma cell proliferation and motility

Wang

et al. 2015

Molecular Medicine Reports

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Meningiomas are common types of intracranial tumor. Invasive and malignant meningiomas present a significant therapeutic challenge due to high rates of recurrence and invasion. Understanding the molecular mechanism of invasion may assist in designing novel therapeutic approaches and improving patient survival rates. The HER‑2 gene has been demonstrated to be a useful predictor of tumor aggression, which promotes the survival and growth of cancer cells through the mitogen‑activated protein kinase and/or phosphatidylinositol 3‑kinase (PI3K)/AKT pathway. Until now, few studies have investigated the associateion between meningiomas and the expression of HER‑2, and the significance of HER‑2 in meningiomas remains to be elucidated. The present study aimed to investigate the effects of the HER‑2 gene on the biological behaviors of human malignant meningioma cells. The results demonstrated that downregulation of the expression of HER‑2 by small interfering RNA in human meningioma cells significantly inhibited cell motility and proliferation, led to cell cycle arrest at the G0/G1‑phase and increased early apoptosis. By contrast, the overexpression of HER‑2 group resulted in meningioma cell invasion, migration and proliferation being significantly enhanced, cell cycle was promoted at the G1/S‑phase and early apoptosis was decreased. Accordingly, the inhibition of HER‑2 also prevented the protein expression of PI3K and phosphorylated AKT. The results demonstrated that regulation of the HER‑2 gene can affect the proliferation, apoptosis, invasion and metastasis abilities of human meningioma cells in vitro. Furthermore, PI3K/AKT may contribute to the carcinogenesis and development of human meningiomas in combination with HER-2.

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Section: Discussionmentioning

confidence: 95%

Role of HER-2 activity in the regulation of malignant meningioma cell proliferation and motility

Wang

et al. 2015

Molecular Medicine Reports

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“…Additionally, an evidence from an earlier research that had evidenced the involvement of CYP4Z1 in tumor angiogenesis and growth in BC (W. Yu et al, ). It is noteworthy that intensification of PI3K/AKT/MAPK signaling cascade accelerates the proliferation, invasion, angiogenesis, and metastasis of BC (Britschgi, Radimerski, & Bentires‐Alj, ; Fu et al, ; Paplomata & O'Regan, ). Consequently, this ceRNET event reveals a new molecular mechanism behind the angiogenesis in BC.…”

Section: Cerna Interplay In Bc Development and Pathogenesismentioning

confidence: 99%

“…. It is noteworthy that intensification of PI3K/AKT/MAPK signaling cascade accelerates the proliferation, invasion, angiogenesis, and metastasis of BC(Britschgi, Radimerski, & Bentires-Alj, 2013;Fu et al, 2014;Paplomata & O'Regan, 2014). Consequently, this ceRNET event reveals a new molecular mechanism behind the angiogenesis in BC.Interestingly, L Zheng et al (2016).…”

mentioning

confidence: 98%

Competing endogenous RNA (ceRNA) cross talk and language in ceRNA regulatory networks: A new look at hallmarks of breast cancer

Abdollahzadeh

Daraei

Mansoori

et al. 2018

Journal Cellular Physiology

229

185

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Breast cancer (BC) is the most frequently occurring malignancy in women worldwide. Despite the substantial advancement in understanding the molecular mechanisms and management of BC, it remains the leading cause of cancer death in women. One of the main reasons for this obstacle is that we have not been able to find the Achilles heel for the BC as a highly heterogeneous disease. Accumulating evidence has revealed that noncoding RNAs (ncRNAs), play key roles in the development of BC; however, the involving of complex regulatory interactions between the different varieties of ncRNAs in the development of this cancer has been poorly understood. In the recent years, the newly discovered mechanism in the RNA world is “competing endogenous RNA (ceRNA)” which proposes regulatory dialogues between different RNAs, including long ncRNAs (lncRNAs), microRNAs (miRNAs), transcribed pseudogenes, and circular RNAs (circRNAs). In the latest BC research, various studies have revealed that dysregulation of several ceRNA networks (ceRNETs) between these ncRNAs has fundamental roles in establishing the hallmarks of BC development. And it is thought that such a discovery could open a new window for a better understanding of the hidden aspects of breast tumors. Besides, it probably can provide new biomarkers and potential efficient therapeutic targets for BC. This review will discuss the existing body of knowledge regarding the key functions of ceRNETs and then highlights the emerging roles of some recently discovered ceRNETs in several hallmarks of BC. Moreover, we propose for the first time the “ceRnome” as a new term in the present article for RNA research.

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“…In vitro kinase assay conformed that KU004 was a potent dual EGFR/HER2 inhibitor (Data unshown). Previous studies in our lab have demonstrated that KU004 could inhibit the proliferation of human breast cancer SKBR3 cells in vitro by inducing G 1 phase arrest [21]. However, the effects of KU004 on other human cancer cells in vitro and the underlying molecular mechanisms involved are still unknown.…”

Section: Introductionmentioning

confidence: 94%

A novel dual EGFR/HER2 inhibitor KU004 induces cell cycle arrest and apoptosis in HER2-overexpressing cancer cells

et al. 2015

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Human epidermal growth factor receptor 2 (HER2) is a validated therapeutic target in cancer therapy, and HER2 protein-tyrosine kinase inhibitors have attracted considerable attention in the field of searching for novel anticancer drug candidates. In this study, we investigated the anticancer effect of KU004, a novel dual EGFR and HER2 inhibitor in vitro and in vivo. In vitro, KU004 preferentially inhibited the growth of HER2-overexpressing breast and gastric cell lines and HER2 expression level significantly correlated with response to KU004. It blocked activation of EGFR, HER2 and downstream Akt and Erk and induced G0/G1 arrest which was associated with downregulation of p53, p21, cyclin D1 and CDK4 along with increase of p27 and dephosphorylation of pRb. Apoptosis occurred in a caspase-dependent manner mainly via the extrinsic apoptotic pathway after KU004 treatment. The in vitro efficacy of KU004 was comparable to that of lapatinib. Moreover, KU004 suppressed the growth of NCI-N87 tumor and induced apoptosis without causing apparent weight loss or obvious toxicity. Tumor volume was significantly smaller in KU004-treated group than that in lapatinib-treated group at comparable dose levels. Taken together, these findings demonstrate KU004 can be expected to be a promising anti-HER2 candidate.

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KU004 induces G1 cell cycle arrest in human breast cancer SKBR-3 cells by modulating PI3K/Akt pathway

Cited by 8 publications

References 23 publications

Role of HER-2 activity in the regulation of malignant meningioma cell proliferation and motility

Role of HER-2 activity in the regulation of malignant meningioma cell proliferation and motility

Competing endogenous RNA (ceRNA) cross talk and language in ceRNA regulatory networks: A new look at hallmarks of breast cancer

A novel dual EGFR/HER2 inhibitor KU004 induces cell cycle arrest and apoptosis in HER2-overexpressing cancer cells

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