Poster Presentation 35th Lorne Cancer Conference 2023

mTORC1 differentially regulates ferroptosis induced by inhibition of GPX4 or SLC7A11 (#168)

Thomas Jackson 1 2 , Nicholas Clemons 1 2
  1. Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  2. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia

Ferroptosis is a form of regulated, iron-dependent cell death that is executed by plasma membrane rupture following accumulation of lipid peroxides. Ferroptosis can be triggered through inhibition of GPX4, a glutathione-dependent enzyme that catalyses the reduction of lipid peroxides, or SLC7A11, a plasma membrane cystine transporter that supports GPX4 activity by promoting glutathione synthesis. Cancer cells that acquire resistance to traditional chemotherapies can remain sensitive to ferroptosis, positioning induction of ferroptosis as a promising therapeutic strategy for cancer treatment. The sensitivity of cancer cells to ferroptosis is intimately tied to the metabolic state of the cell, meaning that understanding how different metabolic and signalling pathways affect sensitivity to ferroptosis will be crucial if this form of cell death is to be exploited therapeutically. mTORC1, a protein complex that controls cell metabolism and growth in response to growth factor signalling and intracellular nutrient availability, appears to modulate sensitivity to ferroptosis. However, published reports are contradictory with regards to whether mTORC1 activity enhances or suppresses ferroptosis. To resolve these discrepancies, we investigated the effect of mTORC1 inhibition on the sensitivity of cancer cells to ferroptosis induced by inhibition of SLC7A11 or GPX4. Surprisingly, mTORC1 inhibition could either suppress or enhance ferroptosis depending on the method of induction. Specifically, ferroptosis induced by inhibition of SLC7A11 was delayed by mTORC1 inhibition, while ferroptosis induced by inhibition of GPX4 was accelerated and enhanced. Similar results were obtained in experiments performed in culture media lacking serum, which contains growth factors that regulate mTOR activity. These results suggest that the forms of ferroptosis induced by inhibition of SLC7A11 or GPX4 are subjected to distinct or even opposing regulation, despite their convergence at the level of lipid peroxidation and plasma membrane rupture.