Abstract 5480: Colorectal cancer cell lines harboring mutation in Wnt/β-catenin pathway shows enhanced sensitivity to the stearoyl-CoA desaturase (SCD) inhibitor, DSP-0692

• Published in: Cancer research (Chicago, Ill.) Ill.), 2018-07, Vol.78 (13_Supplement), p.5480-5480
• Main Authors: Furuta, Yudai, Fukunaga, Yuichi, Ikeda, Satoshi, Koga, Erina, Umehara, Hiroki, Otsubo, Tsuguteru, Watanabe, Manabu, Hasegawa, Futoshi, Ban, Hitoshi, Sugaru, Eiji
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2018-5480

Colorectal cancer (CRC) is one of the most frequent malignant diseases worldwide. Recent studies suggest that a small subpopulation of cells known as cancer stem cells (CSCs) may promote the high metastasis and relapse associated with CRC. It has been reported that Wnt/β-catenin signaling is aberrantly activated in a variety of cancer including colorectal cancer, and plays a critical role in CSC maintenance. Here it is shown that a novel SCD inhibitor, DSP-0692, may inhibited Wnt/β-catenin signaling pathway through two different mechanisms in CRC. The effect of SCD inhibition on Wnt3A secretion, in which process post-translational fatty acylation (with palmitoleic acid) is required, was investigated. DSP-0692 led to reduced Wnt3A protein levels secreted in the media in Wnt3A-overexpressing cell line. This result was further confirmed by the TCF/LEF reporter assay in HCT116 incubated with conditional media from L-Wnt3A cells, with or without DSP-0692. DSP-0692 also inhibited exogenous Wnt3A-induced reporter activity. This indicates DSP-0692 may inhibit the β-catenin/Tcf transactivation by additional mechanism in addition to inhibiting Wnt secretion. To clarify this additional mechanism, the effect of DSP-0692 on nuclear translocation of β-catenin was investigated. SCD inhibition led to a decrease of β-catenin amounts within the nucleus. Currently, how SCD inhibition affects nuclear translocation of β-catenin is being investigated. It was confirmed that DSP-0692 exhibited lower IC50 value to sphere cells carrying mutations related to Wnt/β-catenin signaling pathway than those without these mutations. Next, the effect of SCD inhibition on Wnt/β-catenin signaling pathway in vivo was investigated. Treatment with DSP-0692 in a SW620 colorectal cancer xenograft model suppressed mRNA expression of the Wnt/β-catenin target genes, as well as CSC marker gene. Taken together, these results suggest fatty acid desaturation in tumor cells may have an impact on Wnt/β-catenin signaling pathway and involve in CSC maintenance. The approaches targeting SCD could be a new therapeutic strategy for anti-CSC therapy in CRC. Citation Format: Yudai Furuta, Yuichi Fukunaga, Satoshi Ikeda, Erina Koga, Hiroki Umehara, Tsuguteru Otsubo, Manabu Watanabe, Futoshi Hasegawa, Hitoshi Ban, Eiji Sugaru. Colorectal cancer cell lines harboring mutation in Wnt/β-catenin pathway shows enhanced sensitivity to the stearoyl-CoA desaturase (SCD) inhibitor, DSP-0692 [abstract]. In: Proceedings of the