Exosomal neutral sphingomyelinase 1 suppresses hepatocellular carcinoma via decreasing the ratio of sphingomyelin/ceramide

Abstract

Neutral sphingomyelinase 1 (NSMase1) mediates caspase-3 activation and apoptosis. However, the role of NSMase1, especially exosome-borne NSMase1 in hepatocellular carcinoma (HCC), remains unclear. We report that NSMase1, which converts sphingomyelin (SM) to ceramide, was significantly downregulated in HCC tissues. Low NSMase1 expression predicted poor long-term survival of HCC patients. NSMase1 downregulation in HCC resulted in increased SM and reduced ceramide (Cer) that led to an increased SM/Cer ratio. Interestingly, NSMase1 and NSMase activity were also decreased in exosomes isolated from HCC tissues and cell lines. Furthermore, NSMase activity increased in exosomes isolated from the culture medium of L02 cells transfected with pEGFP-C3-NSMase1 (NSMase1-Exo). NSMase1-Exo suppressed HCC cell growth and induced apoptosis via reduction of the SM/Cer ratio. Thus, NSMase1 in exosomes inhibits HCC growth by decreasing the SM/Cer ratio.

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

“…It is well-known that SGMS2 is a key enzyme in the hemeostasis of Cer, which is tightly associated with cell apoptosis 5,11 . Many studies have revealed that ceramide plays a pivotal role in cell apoptosis via the P-AKT → caspase-3 → PARP signalling pathway in several types of diseases, including renal cell carcinoma 12 , hepatocellular carcinoma 13,14 and retinopathy 15 . To determine the mechanism underlying the SGMS2-induced increase in cell proliferation, we investigated the expression of Cer and activation of the Cer-associated apoptosis pathway.…”

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.…”

Sphingomyelinases and Liver Diseases

“…Targeting ACDase, an enzyme that hydrolyzes ceramide (Figure 1), with LCL521 or carmofur has been shown to be of potential relevance in cancer [106,107]. Furthermore, NSMase-1 was reported to be downregulated in HCC tissues [108], and NSMase-2 deficiency promotes liver tumor development by regulating the survival and proliferation of cancer stem-like cells [109]. Despite these findings, many solid tumors, including HCC, develop strategies contributing to the development of chemoresistance.…”

“…In addition, recombinant human ASMase has emerged as a potential adjuvant treatment with sorafenib in HCC [121]. Moreover, exosomal NSMase-1 has been reported to suppress HCC via decreasing the ratio of SM/ceramide [108]. Overall, although there are emerging data regarding the role of SMases in HCC, further understanding about this link is still needed to optimize the targeting of SLs/SMases as potential therapeutics.…”