Targeting a Lipid Desaturation Enzyme, SCD1, Selectively Eliminates Colon Cancer Stem Cells through the Suppression of Wnt and NOTCH Signaling

Abstract

The elimination of the cancer stem cell (CSC) population may be required to achieve better outcomes of cancer therapy. We evaluated stearoyl-CoA desaturase 1 (SCD1) as a novel target for CSC-selective elimination in colon cancer. CSCs expressed more SCD1 than bulk cultured cells (BCCs), and blocking SCD1 expression or function revealed an essential role for SCD1 in the survival of CSCs, but not BCCs. The CSC potential selectively decreased after treatment with the SCD1 inhibitor in vitro and in vivo. The CSC-selective suppression was mediated through the induction of apoptosis. The mechanism leading to selective CSC death was investigated by performing a quantitative RT-PCR analysis of 14 CSC-specific signaling and marker genes after 24 and 48 h of treatment with two concentrations of an inhibitor. The decrease in the expression of Notch1 and AXIN2 preceded changes in the expression of all other genes, at 24 h of treatment in a dose-dependent manner, followed by the downregulation of most Wnt- and NOTCH-signaling genes. Collectively, we showed that not only Wnt but also NOTCH signaling is a primary target of suppression by SCD1 inhibition in CSCs, suggesting the possibility of targeting SCD1 against colon cancer in clinical settings.

Wnt Signaling: From Mesenchymal Cell Fate to Lipogenesis and Other Mature Adipocyte Functions

“…Thus, endogenous Wnt signaling within adipocytes appears to be an important regulator of palmitoleic acid formation. Interestingly, the reciprocal relationship has also been shown in the cancer field: Wnt secretion and subsequent functionality depend on lipid modification with SCD1-derived palmitoleic acid (60). These findings suggest the existence of Wnt-mediated cross talk between adipose tissues and cancers.…”

Increased Lipogenesis is Critical for Self-Renewal and Growth of Breast Cancer Stem Cells: Impact of Omega-3 Fatty Acids

“…Particularly, the enhanced synthesis of MUFA by the upregulation of the lipogenic enzyme, SCD1, seems to be a key mechanism for CSC to produce building materials (ie, components of cell membrane) to meet their need for rapid self‐renewal and growth 57 . Suppression of SCD1 is also shown to inhibit the growth of colon cancer stem cells via Notch/Wnt signaling pathways 58 and enhances the efficacy of chemotherapy for treating lung cancer stem cells through autophagy as well as ER stress 59 . This notion is also supported by other studies showing that SCD1 is overexpressed in various types of malignant cells and that selective inhibition of this enzyme exerts anticancer effects 60,61 .…”

Role of Intra- and Extracellular Lipid Signals in Cancer Stemness and Potential Therapeutic Strategy

“…It has been observed that the expression of SCD1 is upregulated in hepatocellular, renal clear cell, lung, prostate and breast cancer, which is associated with poorer prognosis (Fritz et al, 2010;Holder et al, 2013;von Roemeling et al, 2013;Huang et al, 2015;Wohlhieter et al, 2020). Recent evidence also supported that SCD1 involved in many tumor-related pathways and played important roles in the self-renewal, metastasis, and resistance to therapy in glioblastoma, breast, lung and bladder CSCs (Noto et al, 2013;Colacino et al, 2016;Li J. et al, 2017;Mukherjee et al, 2017;Noto et al, 2017;Pisanu et al, 2018;Pinkham et al, 2019;Gao et al, 2020;Yu et al, 2021).…”

“…Accumulating evidence has proved that several signaling pathways are closely related to SCD1. The inhibition of SCD1 led to the selective elimination of colon CSCs through suppressing Wnt and Notch signaling ( Yu et al, 2021 ). The results showed that the crosstalk between SCD1 and Hippo pathway played an important role in maintaining the stemness features of the lung, gastric, and melanoma CSCs ( Noto et al, 2017 ; Pisanu et al, 2018 ; Gao et al, 2020 ).…”