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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 2/2021

01-02-2021 | Hepatocellular Carcinoma | Original Article

Overriding sorafenib resistance via blocking lipid metabolism and Ras by sphingomyelin synthase 1 inhibition in hepatocellular carcinoma

Authors: Haofeng Lu, Lin Zhou, Hongping Zuo, Wenjin Le, Jianfei Hu, Tiequan Zhang, Mi Li, Yufeng Yuan

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2021

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Abstract

Background

The survival benefit of sorafenib, the most used drug for advanced hepatocellular carcinoma (HCC), is unsatisfactory due to the development of adaptive resistance. Exploring the mechanisms underlying sorafenib resistance is important to develop sensitizing strategy. Sphingomyelin synthase (SMS) plays a critical role in sphingolipid metabolism which is involved in oncogenesis and drug resistance.

Methods

SMS1 and SMS2 levels in HCC cells in response to prolonged chemotherapy were analyzed using ELISA. mRNA and protein levels of SMS in HCC and adjacent normal tissues were analyzed by ELISA and real-time PCR. The roles of SMS and its downstream targets were investigated using cellular and biochemical assays and mass spectrometry.

Results

SMS1, but not SMS2, was upregulated in HCC in response to sorafenib treatment, although HCC displayed similar RNA and protein level of SMS1 compared to adjacent normal liver tissues. Overexpression of SMS1 promoted HCC growth and migration, and alleviated sorafenib’s toxicity. SMS1 inhibition via genetic and pharmacological approaches consistently resulted in inhibition of growth and migration, and apoptosis induction in sorafenib-resistance HCC cells. SMS1 inhibition also augmented the efficacy of sorafenib in sensitive HCC cells. SMS1 inhibition disrupted sphingolipid metabolism via accumulating ceramide and decreasing sphingomyelin, inducing mitochondrial dysfunction and oxidative stress, and decreasing Ras activity in resistant cells. Overexpression of constitutively active Ras reversed the inhibitory effects of SMS1 inhibition. Although SMS1 overexpression did not affect Ras expression and activity, Pearson correlation coefficient analysis of SMS1 and Ras expression demonstrated that there was positive correlation between SMS1 and RAS (NRAS, R = 0.55, p < 0.01; KRAS, R = 0.44, p < 0.01).

Conclusions

Our work is the first to suggest that SMS1 plays a more important role in sorafenib resistance than tumorigenesis, and provides preclinical evidence to overcome sorafenib resistance with SMS1 inhibition in HCC.
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Metadata
Title
Overriding sorafenib resistance via blocking lipid metabolism and Ras by sphingomyelin synthase 1 inhibition in hepatocellular carcinoma
Authors
Haofeng Lu
Lin Zhou
Hongping Zuo
Wenjin Le
Jianfei Hu
Tiequan Zhang
Mi Li
Yufeng Yuan
Publication date
01-02-2021
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 2/2021
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-020-04199-6

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