Mechanism of sorafenib resistance associated with ferroptosis in HCC

Abstract

Hepatocellular carcinoma (HCC) is the most familiar primary hepatic malignancy with a poor prognosis. The incidence of HCC and the associated deaths have risen in recent decades. Sorafenib is the first drug to be approved by the Food and Drug Administration (FDA) for routine use in the first-line therapy of patients with advanced HCC. However, only about 30% of patients with HCC will be benefited from sorafenib therapy, and drug resistance typically develops within 6 months. In recent years, the mechanisms of resistance to sorafenib have gained the attention of a growing number of researchers. A promising field of current studies is ferroptosis, which is a novel form of cell death differing from apoptosis, necroptosis, and autophagy. This process is dependent on the accumulation of intracellular iron and reactive oxygen species (ROS). Furthermore, the increase in intracellular iron levels and ROS can be significantly observed in cells resistant to sorafenib. This article reviews the mechanisms of resistance to sorafenib that are related to ferroptosis, evaluates the relationship between ferroptosis and sorafenib resistance, and explores new therapeutic approaches capable of reversing sorafenib resistance in HCC through the modulation of ferroptosis.

Keywords: ROS; ferroptosis; hepatocellular carcinoma; sorafenib; sorafenib resistance.

FIGURE 1

Sorafenib resistance pathways associated with ferroptosis. YAP/TAZ is firstly phosphorylated by Hippo signaling, then transported into the nucleus by NPCs. YAP/TAZ can activate ATF4 in the nucleus or bind to TEAD to induce the expression of SLC7A11 and raise intracellular GSH levels. LCN2 can inhibit the activity of the transferrin receptor, and the deletion of LIFR will activate the NF-κB signaling pathway, leading to the upregulation of LCN2 expression, thus reducing the intracellular iron entrance and inhibiting the occurrence of ferroptosis in cells. When the Keap1-Nrf2 system is activated, the expression of its downstream genes related to ferroptosis, such as MT-1G, ABCC5, and GPX4, will be increased. MT-1G can prevent the lipid peroxidation process in HCC cells. ABCC5 can stabilize the SLC7A11 protein for a more stable action.

FIGURE 2

Part of potential pathways to reverse sorafenib resistance by inducing ferroptosis. Sorafenib has synergistic effects with sulfasalazine in that they both induce AMPK phosphorylation of T172, reduce the expression of transcription factor SREBP1, block BCAT2 transcription in the nucleus, reduce intracellular Glu synthesis, and decrease the xCT system activity. NHE inhibitors like amiloride can inhibit macropinocytosis, block the extra acquisition of cysteine by HCC cells, reduce intracellular cysteine levels, and increase lipid peroxidation production. In addition, metformin also modulates the p62-Keap1-NRF2 pathway and decreases HO-1 expression, thereby regulating the ROS response and inducing more ferroptosis in HCC cells.

FIGURE 3

Inhibition of CISD2 restores sorafenib-induced ferroptosis. Inhibition of CISD2 promotes the action of the autophagy regulator Beclin 1, which facilitates the initiation of autophagy in sorafenib-resistant HCC cells, leading to an increase in the intracellular iron content, provoking Fenton response, inducing oxidative stress, and triggering the development of more ferroptosis.