mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation

Abstract

Glutathione peroxidase 4 (GPX4) utilizes glutathione (GSH) to detoxify lipid peroxidation and plays an essential role in inhibiting ferroptosis. As a selenoprotein, GPX4 protein synthesis is highly inefficient and energetically costly. How cells coordinate GPX4 synthesis with nutrient availability remains unclear. In this study, we perform integrated proteomic and functional analyses to reveal that SLC7A11-mediated cystine uptake promotes not only GSH synthesis, but also GPX4 protein synthesis. Mechanistically, we find that cyst(e)ine activates mechanistic/mammalian target of rapamycin complex 1 (mTORC1) and promotes GPX4 protein synthesis at least partly through the Rag-mTORC1-4EBP signaling axis. We show that pharmacologic inhibition of mTORC1 decreases GPX4 protein levels, sensitizes cancer cells to ferroptosis, and synergizes with ferroptosis inducers to suppress patient-derived xenograft tumor growth in vivo. Together, our results reveal a regulatory mechanism to coordinate GPX4 protein synthesis with cyst(e)ine availability and suggest using combinatorial therapy of mTORC1 inhibitors and ferroptosis inducers in cancer treatment.

Kaempferol Ameliorates Oxygen-Glucose Deprivation/Reoxygenation-Induced Neuronal Ferroptosis by Activating Nrf2/SLC7A11/GPX4 Axis

“…However, it remains unclear whether kaempferol suppresses OGD/R-induced ferroptosis. GPX4 is very important for regulating ferroptosis and SLC7A11 acts as an upstream mediator of GPX4 [22]. In addition, Nrf2 can inhibit ferroptosis via regulation of SLC7A11 [10,23].…”

KEAP1 deficiency drives glucose dependency and sensitizes lung cancer cells and tumors to GLUT inhibition

“…Cystine uptake using [ 14 C]cystine (Perkin Elmer) was conducted as described previously (Zhang et al, 2018(Zhang et al, , 2021. Glucose uptake was conducted similar to cystine uptake.…”

mTORC1 and ferroptosis: Regulatory mechanisms and therapeutic potential

“…However, this simple view was challenged by the observation that GSH depletion generally induces much milder ferroptotic cell death than does cystine starvation or class 1 FIN treatment, or even fails to cause significant cell death in certain cancer cell lines, [51] raising the question of whether the anti-ferroptosis role of SLC7A11-mediated cystine uptake involves other unknown mechanisms. A recent study by Zhang et al partly fills in this knowledge gap by showing that cyst(e)ine promotes not only GSH synthesis but also GPX4 protein synthesis through the Rag-mTORC1-4EBP signaling pathway [46] (Figure 2A). In that study, proteomic analyses revealed that GPX4 protein level was significantly downregulated upon cystine starvation, which was further confirmed by either erastin treatment or SLC7A11 knockdown.…”

“…Notably, a series of recent studies revealed intriguing interplays between mTORC1 signaling and ferroptosis. [46][47][48][49] In the following sections, we summarize these recent findings linking mTORC1 to ferroptosis, analyze the seemingly context-dependent role of mTORC1 in either suppressing or promoting ferroptosis, and discuss the potential of combining mTORC1 inhibitors and FINs in cancer therapy.…”

“…As described below, three recent studies revealed that mTORC1 acts as a negative regulator of ferroptosis in cancer cells and that the regulation of ferroptosis by mTORC1 can involve several mechanisms. [46][47][48]…”