Abstract
The influence of cell membrane fluidity on cancer progression has been established in different solid tumors. We previously reported that “cancer-associated fibroblasts” (CAFs) induced epithelial-mesenchymal transition and increased cell membrane fluidity and migration in poorly (MCF-7) and highly invasive (MDA-MB-231) breast cancer cells. We also found that the membrane fluidity regulating enzyme stearoyl-CoA desaturase 1 (SCD1) was upregulated in tumor cells co-cultured with CAFs and established its essential role for both intrinsic and CAF-driven tumor cell motility. Here, we further explored the mechanisms involved in the SCD1-based modulation of breast cancer cell migration and investigated the role of the other human SCD isoform, SCD5. We showed that the addition of oleic acid, the main SCD1 product, nullified the inhibitory effects produced on MCF-7 and MDA-MB-231 cell migration by SCD1 depletion (pharmacological or siRNA-based). Conversely, SCD5 seemed not involved in the regulation of cancer cell motility. Interestingly, a clear induction of necrosis was observed as a result of the depletion of SCD5 in MCF-7 cells, where the expression of SCD5 was found to be upregulated by CAFs. The necrotic effect was rescued by a 48-h treatment of cells with oleic acid. These results provide further insights in understanding the role of SCD1 in both intrinsic and CAF-stimulated mammary tumor cell migration, unveiling the metabolic basis of this desaturase-triggered effect. Moreover, our data suggest the ability of CAFs to promote the maintenance of tumor cell survival by the induction of SCD5 levels.
Highlights
Metastatic progression is mostly responsible for the fatal outcome of human carcinomas and it is driven by an improved cancer cell migration ability
Since we recently demonstrated that pharmacological or genetic inactivation of stearoyl-CoA desaturase 1 (SCD1) resulted in a significant inhibition of both intrinsic and CAFpromoted MCF-7 and MDA-MB-231 cell migration [19], here we sought to address whether this effect was due to the deficiency in oleic acid, the main product of Stearoyl-CoA desaturase (SCD) activity
In the two above described cell lines, we found that the inhibitory effect produced on tumor cell migration by SCD1 depletion is ascribable to the resulting deficiency of oleic acid, the main product of the desaturase enzymatic activity
Summary
Metastatic progression is mostly responsible for the fatal outcome of human carcinomas and it is driven by an improved cancer cell migration ability In this respect, the key role played by the interaction between the epithelial tumor cells and the stromal microenvironment has been established in different malignancies, with a stroma-triggered induction of tumor cell migration/. We previously reported an overall pro-invasive effect exerted on mammary cancer cells by the main elements of the tumor stroma, the so-called “cancerassociated fibroblasts” (CAFs), as they were able to induce “epithelial-mesenchymal transition” (EMT) and an increase in membrane fluidity, as well as in migration speed and directness [18]. Consistent with the induction of a more loose packing of the membrane lipid bilayer in mammary cancer cells, we previously showed the ability of CAFs to promote SCD1 upregulation and demonstrated the key role played by the desaturase in both intrinsic and CAF-prompted tumor cell migration. We found that either siRNA-mediated or pharmacological inhibition of SCD1 impaired tumor cell migration [19]
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