A Marine Terpenoid, Heteronemin, Induces Both the Apoptosis and Ferroptosis of Hepatocellular Carcinoma Cells and Involves the ROS and MAPK Pathways.

Wen-Tsan Chang,Yi-Hua Chang,Pei-Jung Fu,Chang-Yi Wu,Yen-Ni Teng,Mei-Chin Lu,Yung-Ding Bow,Chia-Yang Li,Chien-Chih Chiu,Ruei-Nian Li,Yi-Chang Liu,Cristina Angeloni

doi:10.1155/2021/7689045

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of death, resulting in over 700 thousand deaths annually worldwide. Chemotherapy is the primary therapeutic strategy for patients with late-stage HCC. Heteronemin is a marine natural product isolated from Hippospongia sp. that has been found to protect against carcinogenesis in cholangiocarcinoma, prostate cancer, and acute myeloid leukemia. In this study, heteronemin was found to inhibit the proliferation of the HCC cell lines HA22T and HA59T and induce apoptosis via the caspase pathway. Heteronemin treatment also induced the formation of reactive oxygen species (ROS), which are associated with heteronemin-induced cell death, and to trigger ROS removal by mitochondrial SOD2 rather than cytosolic SOD1. The mitogen-activated protein kinase (MAPK) signaling pathway was associated with ROS-induced cell death, and heteronemin downregulated the expression of ERK, a MAPK that is associated with cell proliferation. Inhibitors of JNK and p38, which are MAPKs associated with apoptosis, restored heteronemin-induced cell death. In addition, heteronemin treatment reduced the expression of GPX4, a protein that inhibits ferroptosis, which is a novel form of nonapoptotic programmed cell death. Ferroptosis inhibitor treatment also restored heteronemin-induced cell death. Thus, with appropriate structural modification, heteronemin can act as a potent therapeutic against HCC.

Highlights

Natural products are the leading source of chemotherapy drugs [1,2,3,4]
We demonstrate that the anticancer effect of heteronemin on Hepatocellular carcinoma (HCC) is associated with reactive oxygen species (ROS)-associated mitogen-activated protein kinase (MAPK) activation and that heteronemin induces HCC death through apoptosis as well as ferroptosis
Significant cell death was observed in both HA22T and HA59T cells after the heteronemin treatment, and HA59T cells exhibited higher sensitivity to heteronemin (Figures 1(a) and 1(b))

Summary

Introduction

Natural products are the leading source of chemotherapy drugs [1,2,3,4]. Natural marine products have been found to have bioactivity against cancer progression [6, 7]; for example, makaluvamines, a group of pyrroloiminoquinone alkaloids isolated from marine sponges, have been identified to induce DNA cleavage [8] and protect against skin cancer [9] and lung cancer [10]. Topoisomerase II, which is associated with DNA replication [16], has been found to be inhibited by the heteronemin treatment [12], and topoisomerase II inhibition is the mechanism underlying the effect of many clinical anticancer drugs, such as topotecan and irinotecan, which are topoisomerase I inhibitors [17, 18].

Methods

Results

Conclusion