N-(3,4-dimethoxyphenethyl)-6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine inhibits bladder cancer progression by suppressing YAP1/TAZ,Genes to Cells

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N-(3,4-dimethoxyphenethyl)-6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine inhibits bladder cancer progression by suppressing YAP1/TAZ
Genes to Cells ( IF 1.3 ) Pub Date : 2022-08-10 , DOI: 10.1111/gtc.12979
Yusuke Shiraishi _{1,

2} , Tomohiko Maehama ₁ , Miki Nishio ₁ , Junji Otani ₁ , Hiroki Hikasa ₃ , Tak Wah Mak _{4,

5,

6,

7} , Takehiko Sasaki ₈ , Teruki Honma ₉ , Yasumitsu Kondoh ₁₀ , Hiroyuki Osada _{10,

11} , Minoru Yoshida _{12,

13} , Masato Fujisawa ₂ , Akira Suzuki ₁

Affiliation

Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan.
Department of Biochemistry, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan.
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Department of Pathology, LKS Faculty of Medicine, University of Hong Kong, Hong Kong.
Department of Biochemical Pathophysiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
RIKEN Center for Biosystems Dynamics Research, Yokohama, Japan.
Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Wako, Japan.
Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Japan.
Department of Biotechnology, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan.

Bladder cancer (BlC) is the fourth most common cancer in males worldwide, but few systemic chemotherapy options for its effective treatment exist. The development of new molecularly-targeted agents against BlC is therefore an urgent issue. The Hippo signaling pathway, with its upstream LATS kinases and downstream transcriptional co-activators YAP1 and TAZ, plays a pivotal role in diverse cell functions, including cell proliferation. Recent studies have shown that overexpression of YAP1 occurs in advanced BlCs and is associated with poor patient prognosis. Accessing data from our previous screening of a chemical library of compounds targeting the Hippo pathway, we identified DMPCA (N-(3,4-dimethoxyphenethyl)-6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine) as an agent able to induce the phosphorylation of LATS1 and YAP1/TAZ in BlC cells, thereby suppressing their viability both in vitro and in mouse xenografts. Our data indicate that DMPCA has a potent anti-tumor effect, and raise the possibility that this agent may represent a new and effective therapeutic option for BlC.

中文翻译：

N-(3,4-二甲氧基苯乙基)-6-甲基-2,3,4,9-四氢-1H-咔唑-1-胺通过抑制 YAP1/TAZ 抑制膀胱癌进展

膀胱癌 (BlC) 是全世界男性中第四大最常见的癌症，但对其有效治疗的全身化疗选择很少。因此，开发新的针对 BlC 的分子靶向药物是一个紧迫的问题。Hippo 信号通路及其上游 LATS 激酶和下游转录共激活因子 YAP1 和 TAZ，在包括细胞增殖在内的多种细胞功能中起着关键作用。最近的研究表明，YAP1 的过度表达发生在晚期 BlC 中，并且与患者预后不良有关。从我们之前筛选的针对 Hippo 途径的化合物化学库中获取数据，我们确定了 DMPCA ( N -(3,4-dimethoxyphenethyl)-6-methyl-2,3,4,9-tetrahydro-1 H-carbazol-1-amine) 作为能够诱导 BLC 细胞中 LATS1 和 YAP1/TAZ 磷酸化的试剂，从而抑制它们在体外和小鼠异种移植物中的生存能力。我们的数据表明 DMPCA 具有强大的抗肿瘤作用，并提高了该药物可能代表 BlC 的一种新的有效治疗选择的可能性。

更新日期：2022-08-10

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