Together we stand, apart we fall: how cell-to-cell contact/interplay provides resistance to ferroptosis

Abstract

Contextualisation of the new type of cell death called “ferroptosis” opened a completely new avenue for the development of anti-cancer therapies. Cumulative fundamental research dating back to the mid-20th century, crowned by the extraordinary work of the group led by Dr. Stockwell from Columbia University in 2012, finally got its candidature to be applied in the clinical settings. Although the potential for clinical importance is undoubtedly growing every day, as showed by the increasing number of papers dealing with ferroptosis and its applications, long experience of cancer research and treatment taught us that caution is still necessary. The plasticity of the tumour cells, particularly acute, along with its involvement in the resistance mechanisms, that have been seen, to greater or lesser extent, for almost all currently used therapies, represents the biggest fascinations in biomedical research field and also the biggest challenge to achieving cures in cancer patients. Accordingly, the main features of fundamental research have to be vigilance and anticipation. In this review, we tried to summarize the literature data, accumulated in the past couple of years, which point out the pitfalls in which “ferroptosis inducers” can fall if used prematurely in the clinical settings, but at the same time can provide a great advantage in the exhausting battle with cancer resistance. This is the first comprehensive review focusing on the effects of the cell-to-cell contact/interplay in the development of resistance to ferroptosis, while the contribution of cell-born factors has been summarized previously so here we just listed them.

Genetic Disruption of the γ-Glutamylcysteine Ligase in PDAC Cells Induces Ferroptosis-Independent Cell Death In Vitro without Affecting In Vivo Tumor Growth

“…This could be attributed to the lower oxidative pressure that cells experience in these conditions. However, another possibility that became apparent in our previous work with xCT-KO xenografts is cell-to-cell interplay which, in the case of xCT-KO cells, provides them with the source of reduced cysteine [28,38]. Although the degradation of GSH in vivo is just as intensive as in vitro [35,[39][40][41], the continuous flux of GSH from adjacent cells might be a sufficient source of GSH for GCLc-KO cells to survive and thrive in vivo.…”

Anticancer Activity of Urease Mimetic Cobalt (III) Complexes on A549-Lung Cancer Cells: Targeting the Acidic Microenvironment

“…Similarly, Reactive Oxygen Species (ROS) have been well studied in regulating cell death in cancer. Mitochondria, as the major site of Iron-dependent peroxidation of lipids, generates excessive ROS leading to ferroptosis, a necrotic cell death pathway [57]. Hence, the role of mitochondria in targeted cancer therapy is emerging as a promising research area that may contribute to significant outcomes in studies with similar interests.…”

IL-23 signaling prevents ferroptosis-driven renal immunopathology during candidiasis

“…Protrusive force is generated during phagocytosis 80 , and immune cells respond to mechanical forces during the polarized growth of fungal hyphae 81 . Likewise, fungal β-glucan recognition induces mTOR signaling in monocytes 82 , which has been associated with increased sensitivity to ferroptosis 83 . Hence, mechanical forces during infection and consequently activation of distinct downstream signaling pathways sensitize myeloid cells to undergo ferroptotic cell death.…”