YAP promotes erlotinib resistance in human non-small cell lung cancer cells

Hsu, Ping‐Chih; You, Bo; Yang, Yilin; Zhang, Wenqian; Wang, Yucheng; Xu, Zhidong; Dai, Yuyuan; Liu, Shu; Yang, Cheng‐Ta; Li, Hui; Hu, Bin; Jablons, David M.; Li, You

doi:10.18632/oncotarget.10458

Cited by 100 publications

(129 citation statements)

References 29 publications

(32 reference statements)

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“…A number of recent studies have demonstrated that the increased level of YAP was revealed to be associated with increased drug resistance in multiple lines of cancer cells (23,24,29). In the present study, YAP silencing sensitized HCC cells to CDDP, suggesting that YAP induces CDDP resistance in HCC cells.…”

Section: Discussionsupporting

confidence: 63%

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Downregulation of YAP inhibits proliferation, invasion and increases cisplatin sensitivity in human hepatocellular carcinoma cells

Wang¹,

Wu²,

Zhong³

2018

Oncol Lett

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Abstract. Yes-associated protein (YAP) serves an essential role in tumorigenesis. However, the potential role and the molecular mechanism underlying the effect of YAP on hepatocellular carcinoma (HCC) cells have not been elucidated. In the current study, it was revealed that YAP expression was increased significantly in HCC cancer tissues and its overexpression was associated with tumor differentiation. The silencing of YAP by small interferring RNA led to the inhibition of HCC cell growth, which was associated with the promotion of apoptosis. The silencing of YAP also decreased the invasive potential of HCC cells and the activity of the phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) signaling pathway. Furthermore, silencing of YAP increased the chemosensitivity of HCC cells to cisplatin (CDDP) through inactivation of the PI3K/AKT signaling pathway. In vivo studies using PDTX model suggested a promotive role for YAP in the growth of HCC and knockdown of YAP increased the anti-tumor activity of CDDP. Taken together, these results revealed that YAP is overexpressed in HCC, and promotes proliferation, invasion and drug resistance of HCC cells. Inhibition of YAP, alone or in combination with traditional chemotherapy, may effectively combat HCC.

show abstract

Section: Discussionsupporting

confidence: 63%

“…Accumulating evidence has indicated that YAP is involved in drug resistance in a variety of cancer cells (22)(23)(24). The present study examined whether YAP is involved in drug resistance in HCC cells.…”

Section: Downregulation Of Yap Enhances the Sensitivity Of Hcc Cells mentioning

confidence: 94%

Downregulation of YAP inhibits proliferation, invasion and increases cisplatin sensitivity in human hepatocellular carcinoma cells

Wang¹,

Wu²,

Zhong³

2018

Oncol Lett

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“…It has been reported that EGFR and c-Met are involved in cell migration (20,(35)(36)(37)(38). In the present study, we showed that migration of the OSCC cell lines SAS and Ca9-22 was regulated by both the EGFR and c-Met signalling pathways.…”

Section: Discussionsupporting

confidence: 61%

Migration of oral squamous cell carcinoma cells are induced by HGF/c-Met signalling via lamellipodia and filopodia formation

et al. 2017

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Abstract. The activation of receptor tyrosine kinases (RTKs) results in cellular effects including cell proliferation, survival, migration and invasion; RTKs also play an important role in tumourigenesis. It has been reported that EGFR signalling controls the migration of oral squamous cell carcinoma (OSCC) SAS and HSC3 cells but not of HSC4 cells, although the proliferation of HSC4 cells is regulated by EGF/EGFR. In the present study, we investigated the roles of EGFR and the c-Met signalling pathway in cell migration via filopodia and lamellipodia formation, which may be prerequisites for migration. To explore the role of c-Met in cell migration, we inhibited c-Met RTK activity using the c-Met inhibitor SU11274 and activated c-Met using hepatocyte growth factor (HGF) in three OSCC cell lines HSC4, SAS and Ca9-22 and investigated migration potency using a wound healing assay. We showed that inhibition of c-Met significantly suppressed, and activation of c-Met significantly promoted, the migration of OSCC cells. Additionally, the migration of SAS and Ca9-22 cells was inhibited by the EGFR inhibitors AG1478 and cetuximab and promoted by EGF treatment. Moreover, migration potency was correlated with lamellipodia formation. Furthermore, western blot analyses demonstrated that SU11274 decreased and HGF increased lamellipodin protein levels as well as phosphorylated c-Met levels. Collectively, we demonstrated that c-Met signalling induced lamellipodia formation by upregulating lamellipodin, thereby promoting the migration of OSCC cells.

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“…Verteporfin initially was proposed as a YAP1-TEAD complex inhibitor that prevented YAP1-TEAD interaction [24]. Subsequently, more evidence, including our current study, indicated verteporfin can also decrease YAP1 protein level [39]. The mechanism for YAP reduction by verteporfin is through upregulation of 14-3-3σ, which sequesters YAP1 in the cytoplasm and leads to YAP1 degradation [41].…”

Section: Discussionmentioning

confidence: 75%

YAP1 regulates ABCG2 and cancer cell side population in human lung cancer cells

et al. 2016

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A small population of cancer cells called cancer-initiating cells or cancer stem cells (CSCs) are involved in drug resistance, metastasis, and cancer relapse. Finding pathways that regulate CSC is very important for clinical therapy. ATP-binding cassette sub-family G member 2 (ABCG2) plays a role in side population (SP) cell formation and contributes to chemotherapy resistance in common forms of cancer. Yes-associated protein 1 (YAP1) is a major transcriptional effector of the Hippo pathway, which plays important roles in organ size control and tumorigenesis. In this study, we found ABCG2 and YAP1 were both overexpressed in lung cancer SP cells. Disruption of YAP1 expression by siRNA attenuated the expression of ABCG2 transcript and significantly reduced the percentage of SP cells and sphere formation in lung cancer cells. Overexpression of YAP1 in lung cancers led to an increase in ABCG2 expression and increased the percentage of SP cells. However, overexpression of YAP1 in purified non-SP cells did not increase ABCG2 expression and the percentage of SP cells, which may be due to the inhibition of YAP activity through phosphorylation. YAP1 directly transcriptionally regulated ABCG2 by binding to the promoter of ABCG2. Moreover, the YAP1 inhibitor verteporfin and YAP1 siRNA downregulated ABCG2 level through inhibition of YAP1 in lung cancer cells and sensitized them to the chemotherapy drug doxorubicin. Our study adds a new function for YAP1 that may be relevant to drug resistance and cancer therapy through regulation of ABCG2 and side population cell formation in lung cancer.

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YAP promotes erlotinib resistance in human non-small cell lung cancer cells

Cited by 100 publications

References 29 publications

Downregulation of YAP inhibits proliferation, invasion and increases cisplatin sensitivity in human hepatocellular carcinoma cells

Downregulation of YAP inhibits proliferation, invasion and increases cisplatin sensitivity in human hepatocellular carcinoma cells

Migration of oral squamous cell carcinoma cells are induced by HGF/c-Met signalling via lamellipodia and filopodia formation

YAP1 regulates ABCG2 and cancer cell side population in human lung cancer cells

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