Therapy-induced lipid uptake and remodeling underpin ferroptosis hypersensitivity in prostate cancer

Abstract

Background Metabolic reprograming, non-mutational epigenetic changes, increased cell plasticity, and multidrug tolerance are early hallmarks of therapy resistance in cancer. In this temporary, therapy-tolerant state, cancer cells are highly sensitive to ferroptosis, a form of regulated cell death that is caused by oxidative stress through excess levels of iron-dependent peroxidation of polyunsaturated fatty acids (PUFA). However, mechanisms underpinning therapy-induced ferroptosis hypersensitivity remain to be elucidated. Methods We used quantitative single-cell imaging of fluorescent metabolic probes, transcriptomics, proteomics, and lipidomics to perform a longitudinal analysis of the adaptive response to androgen receptor-targeted therapies (androgen deprivation and enzalutamide) in prostate cancer (PCa). Results We discovered that cessation of cell proliferation and a robust reduction in bioenergetic processes were associated with multidrug tolerance and a strong accumulation of lipids. The gain in lipid biomass was fueled by enhanced lipid uptake through cargo non-selective (macropinocytosis, tunneling nanotubes) and cargo-selective mechanisms (lipid transporters), whereas de novo lipid synthesis was strongly reduced. Enzalutamide induced extensive lipid remodeling of all major phospholipid classes at the expense of storage lipids, leading to increased desaturation and acyl chain length of membrane lipids. The rise in membrane PUFA levels enhanced membrane fluidity and lipid peroxidation, causing hypersensitivity to glutathione peroxidase (GPX4) inhibition and ferroptosis. Combination treatments against AR and fatty acid desaturation, lipase activities, or growth medium supplementation with antioxidants or PUFAs altered GPX4 dependence. Conclusions Our work provides mechanistic insight into processes of lipid metabolism that underpin the acquisition of therapy-induced GPX4 dependence and ferroptosis hypersensitivity to standard of care therapies in PCa. It demonstrates novel strategies to suppress the therapy-tolerant state that may have potential to delay and combat resistance to androgen receptor-targeted therapies, a currently unmet clinical challenge of advanced PCa. Since enhanced GPX4 dependence is an adaptive phenotype shared by several types of cancer in response to different therapies, our work might have universal implications for our understanding of metabolic events that underpin resistance to cancer therapies.

Lipid Droplets in Cancer

“…Currently, it is not clear whether any final executioner proteins of ferroptosis exist, since the process essentially depends on the propagation of lipid peroxidation chain reactions and the ultimate failure of protective antioxidant mechanisms, progressively leading to irreparable membrane and organelle dysfunction. Importantly, induction of ferroptosis by inhibition of GPX4 and/or FSP1 is effective at killing multiple types of cancers in vitro and in vivo (Badgley et al 2020;Bersuker et al 2019;Doll et al 2019;Hangauer et al 2017;Tousignant et al 2020;Viswanathan et al 2017;Zhang et al 2019;Zou et al 2019). Thus, the stimulation of ferroptosis in tumors may offer new opportunities for effective cancer treatment.…”

“…Recent findings provide more support for the idea that lipid droplet breakdown regulates ferroptosis sensitivity. Several types of therapy-resistant cancer cells have been shown to be particularly sensitive to ferroptosis (Tousignant et al 2020;Viswanathan et al 2017). Namely, drug-resistant prostate cancer cells undergo an extensive metabolic reprogramming characterized by increased lipid uptake that drives lipid droplet accumulation and phospholipid remodeling.…”

Comprehensive Analysis of Ferroptosis Regulators in Lung Adenocarcinomas Identifies Prognostic and Immunotherapy-Related Biomarkers

“…It is a complex and vulnerable process affected by a variety of crosslinks among lipids, iron, amino acid metabolism and environmental stress (Galluzzi et al, 2018;Hirschhorn and Stockwell, 2019). Although the physiological role and function of ferroptosis in normal mammalian development have not been fully elucidated, emerging evidence has revealed that ferroptosis is implicated in a number neoplastic contexts, including breast cancer, renal cell carcinoma and prostate cancer (Lue et al, 2017;Hultsch et al, 2018;Tousignant et al, 2020). Recent studies have suggested that ferroptosis may play a role in tumor suppression through metabolic regulation and promotion of cell death (Gao et al, 2015;Jiang et al, 2015).…”

Investigating the effects of two novel 4-MMPB analogs as potent lipoxygenase inhibitors for prostate cancer treatment

“…Moreover, 13 S -HODE, the major metabolite of 15-LOX-1 can interact with anti-apoptotic mediators such as B-cell lymphoma 2 (BCL2) and insulin-like growth factor receptor-1 (IGF-1R) which leads to inhibition of apoptotic signaling pathways in PC [ 59 – 61 ]. Additionally, recent studies demonstrated that 15-LOX-1 is one of the fundamental regulators in ferroptosis pathway [ 44 , 62 ], and is involved in PUFA oxidation and pro‐ferroptotic lipid peroxide generation [ 63 ]. In order to better evaluate the efficacy of anti-cancer agents, treatment strategy should also be assessed in animal experimental models [ 64 , 65 ].…”