Solberg Nina Therese, Melheim Maria, Strand Martin Frank, Olsen Petter Angell, Krauss Stefan
Unit for Cell Signaling, Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0372 Oslo, Norway.
Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PO Box 1112 Blindern, 0317 Oslo, Norway.
Cancers (Basel). 2019 Feb 1;11(2):164. doi: 10.3390/cancers11020164.
The majority of colorectal cancers are induced by subsequent mutations in and genes leading to aberrant activation of both canonical WNT and RAS signaling. However, due to induction of feedback rescue mechanisms some cancers do not respond well to targeted inhibitor treatments. In this study we show that the and mutant human colorectal cancer cell line HCT-15 induces canonical WNT signaling through YAP in a MEK dependent mechanism. This inductive loop is disrupted with combined tankyrase (TNKS) and MEK inhibition. RNA sequencing analysis suggests that combined TNKS/MEK inhibition induces metabolic stress responses in HCT-15 cells promoting a positive FOXO3/FOXM1 ratio to reduce antioxidative and cryoprotective systems.
大多数结直肠癌是由 和 基因的后续突变诱导产生的，这些突变会导致经典WNT和RAS信号通路的异常激活。然而，由于反馈拯救机制的诱导，一些癌症对靶向抑制剂治疗反应不佳。在本研究中，我们表明 和 突变的人结直肠癌细胞系HCT-15通过YAP以MEK依赖性机制诱导经典WNT信号通路。这种诱导循环被联合使用端锚聚合酶（TNKS）和MEK抑制所破坏。RNA测序分析表明，联合使用TNKS/MEK抑制可诱导HCT-15细胞中的代谢应激反应，促进FOXO3/FOXM1比值升高，从而降低抗氧化和低温保护系统。
