SPARC regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma.

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.

• Authors: Hong-Wei Hua, Hao-Sheng Jiang, Ling Jia, Yi-Ping Jia, Yu-Lan Yao, Yi-Wen Chen, Feng Jiang, Dong-Qing Lu, Qing Zhou, Ma-Wei Jiang, Gang Ding
• Journal: Cancer biomarkers : section A of Disease markers (Cancer Biomark) Vol. 32 Issue 4 Pg. 425-433 ( 2021) ISSN: 1875-8592 [Electronic] Netherlands
• PMID: 33843664 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Osteonectin
• Reactive Oxygen Species
• SPARC protein, human
• Sorafenib

Topics

• Antineoplastic Agents (pharmacology)
• Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Ferroptosis (drug effects)
• Hep G2 Cells
• Humans
• Liver Neoplasms (drug therapy, metabolism, pathology)
• Osteonectin (metabolism)
• Reactive Oxygen Species (metabolism)
• Sorafenib (pharmacology)