Stearoyl-CoA Desaturase 1 as a Therapeutic Target for the Treatment of Cancer

Abstract

A distinctive feature of cancer cells of various origins involves alterations of the composition of lipids, with significant enrichment in monounsaturated fatty acids. These molecules, in addition to being structural components of newly formed cell membranes of intensely proliferating cancer cells, support tumorigenic signaling. An increase in the expression of stearoyl-CoA desaturase 1 (SCD1), the enzyme that converts saturated fatty acids to ∆9-monounsaturated fatty acids, has been observed in a wide range of cancer cells, and this increase is correlated with cancer aggressiveness and poor outcomes for patients. Studies have demonstrated the involvement of SCD1 in the promotion of cancer cell proliferation, migration, metastasis, and tumor growth. Many studies have reported a role for this lipogenic factor in maintaining the characteristics of cancer stem cells (i.e., the population of cells that contributes to cancer progression and resistance to chemotherapy). Importantly, both the products of SCD1 activity and its direct impact on tumorigenic pathways have been demonstrated. Based on these findings, SCD1 appears to be a significant player in the development of malignant disease and may be a promising target for anticancer therapy. Numerous chemical compounds that exert inhibitory effects on SCD1 have been developed and preclinically tested. The present review summarizes our current knowledge of the ways in which SCD1 contributes to the progression of cancer and discusses opportunities and challenges of using SCD1 inhibitors for the treatment of cancer.

Sterculic Acid: The Mechanisms of Action beyond Stearoyl-CoA Desaturase Inhibition and Therapeutic Opportunities in Human Diseases

“…SCD1 is located in the ER of cells in many tissues (lung, pancreas, skeletal muscle, brain, adipose tissue) while SCD5 is only located in brain and pancreas [14][15][16]. Although a compensatory effect was observed in some breast cancer models, SCD5 [8] is not able to restore the effects of SCD1 deficiency [17]. Recently, it has been described that SCD5 is also expressed in the fetal brain of dogs, bovines, and birds [18].…”

“…SCD1 overexpression is mediated by LXRs, peroxisome proliferator-activated receptors (PPARs), sterol regulatory element-binding proteins (SREBPs), CCAAT/enhancer-binding proteins (C/EBP)α, etc. [8,23,24]. Curiously, C/EBP also downregulates SCD1 expression in liver and udder during E. coli mastitis and is associated with a SREBP-1 downregulated expression [25].…”

“…ER stress activates ubiquitination and proteasomal mechanisms leading to degradation of SCD1 [32]. Glucose, insulin, but also growth factors, or lipids activate SCD1 expression using different signal pathways [8,33]. For example, phosphatidylinositol-3 kinase (PI3K) and mammalian target of rapamycin (mTOR) are activated in response to insulin [34].…”

“…SCD1 inhibitor treatments usually cause sebocyte atrophy, hair loss, and eye dryness [84]. It has also been observed that SCD1 inhibitors abrogate the protective effects of SCD1 on palmitate-induced lipoapoptotic cell death of β-pancreatic cells [85] Furthermore, different studies in breast cancer models have demonstrated an upregulation of SCD5 in human cancer cells [8]. Recently, alternative FA desaturation pathways have been found in tumor cells.…”

Neonatal hyperoxia inhibits proliferation of atrial cardiomyocytes by suppressing fatty acid synthesis

“…Affymetrix arrays, qRT-PCR and immunohistochemistry revealed that neonatal hyperoxia inhibited genes needed for de novo fatty acid synthesis in the atrial but not ventricular cardiomyocytes of mice exposed to neonatal hyperoxia. These included Fasn and Scd1, which are elevated in highly proliferative tumors, increase proliferation when overexpressed and required for the proliferation of non-cardiac cells (43)(44)(45)(46)(47)(48)(49). We thus explored whether the persistent repression of Fasn and Scd1 expression is responsible for the reduced proliferation of left atrial cardiomyocytes in mice exposed to neonatal hyperoxia.…”