Sphingomyelin synthase 2 promotes an aggressive breast cancer phenotype by disrupting the homoeostasis of ceramide and sphingomyelin

Abstract

Breast cancer is the most common type of carcinoma in women worldwide, but the mechanisms underlying tumour development and progression remain unclear. Sphingomyelin synthase 2 (SGMS2) is a crucial regulator involved in ceramide (Cer) and sphingomyelin (SM) homoeostasis that is mostly studied for its role in lipid metabolism. Our primary study indicated that high SGMS2 expression is associated with breast cancer metastasis. Gain- and loss-of-function assays in vitro and in vivo revealed that SGMS2 promotes cancer cell proliferation by suppressing apoptosis through a Cer-associated pathway and promotes cancer cell invasiveness by enhancing epithelial-to-mesenchymal transition (EMT) initiation through the TGF-β/Smad signalling pathway. Further study determined that SGMS2 activated the TGF-β/Smad signalling pathway primarily by increasing TGF-β1 secretion, which was likely associated with aberrant expression of SM. Thus, our findings indicate that SGMS2-mediated activation of the TGF-β/Smad signalling pathway is important in breast cancer progression, which provides new insight into the mechanisms underlying breast cancer metastasis and suggests a possible anticancer therapy for breast cancer.

Secreted sphingomyelins modulate low mammary cancer incidence observed in certain mammals

“…For example, addition of SM to human pancreatic cancer cells was found to potentiate the chemotherapy drug gemcitabine via a mechanism of increased production of ceramide, mitochondrial depolarization, apoptosis, and cell death 22 . This study, as well as most others, evaluated the effects of SM on cancer progression by focusing on the ratio of SM to ceramides, which are known to regulate the apoptotic signaling pathway [23][24][25] . However, since our lipidomics analysis revealed no difference in ceramide species concentrations between CM from non-CP and CP EqMDEC, ceramide levels alone cannot account for the observed difference in cancer cell death upon exposure to non-CP versus CP EqMDEC CM.…”

Lipid composition of the cancer cell membrane

“…Sphingomyelin induces an increase in resistance to chemotherapy, by P-glycoprotein trafficking to plasma membrane lipid rafts and the increase in cell membrane integrity (Modok et al, 2004;Slotte and Ramstedt, 2007). Besides, the increased level of sphingomyelin act as a tumourpromoting factor (Zheng et al, 2019). This pro-malignant activity arises from the decrease of pro-apoptotic ceramide (Woodcock 2006).…”

The Pathophysiological Role of CoA

“…Silencing miR-107/103 in the liver resulted in improved glucose homeostasis and insulin sensitivity, whereas silencing miR107/103 in adipocytes resulted in upregulated expression of caveolin-1, which activates insulin signaling, probably by stabilizing caveolae-associated insulin receptors [165,166]. Moreover, circulating miR-103 has been recently proposed as an early marker of prediabetes mellitus stage [167].…”