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Article type: Research Article
Authors: Hua, Hong-Weia; c; 1 | Jiang, Hao-Shengc; 1 | Jia, Lingc | Jia, Yi-Pingc | Yao, Yu-Lanc | Chen, Yi-Wenc | Jiang, Fengb | Lu, Dong-Qinga | Zhou, Qinga | Jiang, Ma-Weia; * | Ding, Gangc; *
Affiliations: [a] Oncology Department, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China | [b] Clinical Research & Innovation Unit, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Chongming Branch, Shanghai, China | [c] Oncology Department, Shanghai International Medical Center, Shanghai, China
Correspondence: [*] Corresponding authors: Ma-Wei Jiang, Oncology Department of Xinhua Hospital Affiliated to Medical College of Shanghai Jiaotong University, Shanghai, 200092, China. E-mail: jiangmawei@ xinhuamed.com.cn. Gang Ding, Oncology Department, Shanghai International Medical Center, Shanghai, 200120, China. E-mail: [email protected].
Note: [1] These authors contributed equally to this work as the co-first authors.
Abstract: BACKGROUND: Secreted protein acidic and rich in cysteine (SPARC) is implicated in cancer progression, but its role and associated molecular mechanism in the sorafenib sensitivity of hepatocellular carcinoma cells (HCC) remains elusive. METHODS: Human HCC cell lines Hep3B and HepG2 were treated with sorafenib alone or combined with activator or inhibitor of ferroptosis. Cell viability assay, reactive oxygen species (ROS) assay, lactate dehydrogenase (LDH) assay and western blot were used to study the regulatory mechanism of SPARC on HCC cells. RESULTS: Overexpression of SPARC enhanced the cytotoxic effect of sorafenib in Hep3B and HepG2 cells compared with parental cells. Depletion of SPARC decreased the cytotoxic effect of sorafenib in Hep3B and HepG2 cells compared with parental cells. Moreover, overexpression of SPARC significantly induced LDH release, whereas depletion of SPARC suppressed the release of LDH in Hep3B and HepG2 cells. Inhibition of ferroptosis exerted a clear inhibitory role against LDH release, whereas activation of ferroptosis promoted the release of LDH in HCC cells, as accompanied with deregulated expression of ferroptosis-related proteins. Furthermore, overexpression of SPARC induced oxidative stress, whereas depletion of SPARC suppressed the production of ROS. Deferoxamine (DFX)-induced inhibition of ferroptosis suppressed the production of ROS, while activation of ferroptosis promoted the contents of ROS in HCC cells exposed to sorafenib. CONCLUSION: Our findings give a better understanding of ferroptosis and its molecular mechanism in HCC cells that is regulated by SPARC in response to sorafenib.
Keywords: Hepatocellular carcinoma, sorafenib, SPARC, ferroptosis
DOI: 10.3233/CBM-200101
Journal: Cancer Biomarkers, vol. 32, no. 4, pp. 425-433, 2021
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