Phosphocatalytic Kinome Activity Profiling of Apoptotic and Ferroptotic Agents in Multiple Myeloma Cells

Abstract

Through phosphorylation of their substrate proteins, protein kinases are crucial for transducing cellular signals and orchestrating biological processes, including cell death and survival. Recent studies have revealed that kinases are involved in ferroptosis, an iron-dependent mode of cell death associated with toxic lipid peroxidation. Given that ferroptosis is being explored as an alternative strategy to eliminate apoptosis-resistant tumor cells, further characterization of ferroptosis-dependent kinase changes might aid in identifying novel druggable targets for protein kinase inhibitors in the context of cancer treatment. To this end, we performed a phosphopeptidome based kinase activity profiling of glucocorticoid-resistant multiple myeloma cells treated with either the apoptosis inducer staurosporine (STS) or ferroptosis inducer RSL3 and compared their kinome activity signatures. Our data demonstrate that both cell death mechanisms inhibit the activity of kinases classified into the CMGC and AGC families, with STS showing a broader spectrum of serine/threonine kinase inhibition. In contrast, RSL3 targets a significant number of tyrosine kinases, including key players of the B-cell receptor signaling pathway. Remarkably, additional kinase profiling of the anti-cancer agent withaferin A revealed considerable overlap with ferroptosis and apoptosis kinome activity, explaining why withaferin A can induce mixed ferroptotic and apoptotic cell death features. Altogether, we show that apoptotic and ferroptotic cell death induce different kinase signaling changes and that kinome profiling might become a valid approach to identify cell death chemosensitization modalities of novel anti-cancer agents.

Systematic discrimination of the repetitive genome in proximity of ferroptosis genes and a novel prognostic signature correlating with the oncogenic lncRNA CRNDE in multiple myeloma

“…A recent study showed that induction of Ferroptosis in MM cells triggers DNA methylation and histone modification changes associated with cellular senescence ( 4 ). Similarly, a study compared the kinomic activity profile of the natural anticancer agent withaferin A with apoptotic and ferroptotic signatures to predict the mode of cell death in MM cells ( 53 ). Considering this, herein, we investigated the genomic architecture of ferroptosis-related genes and independently constructed a prognostic signature for patient stratification in MM.…”

Withaferin A: A Dietary Supplement with Promising Potential as an Anti-Tumor Therapeutic for Cancer Treatment - Pharmacology and Mechanisms

“… 168 Notably, according to Emilie, due to considerable overlap in ferroptosis and apoptosis kinome activity, WA induces mixed ferroptosis and apoptosis in multiple myeloma cells. 169 …”

Potential application of traditional Chinese medicine in cerebral ischemia—Focusing on ferroptosis

“…For example, Meng et al proposed a high-performance pyrite nanoenzyme can kill tumor cells in an anti-apoptotic manner by inducing ferroptosis (Meng et al, 2021); Bao et al not only verified the self-made nanolongans can carry multiple targeted drugs to the goal sites, but also demonstrated that ferroptosis and apoptosis were both suppression when using a combination of co-targeted anti-cancer therapies (Bao et al, 2019). Logie et al (2021) showed that cell death by apoptosis and ferroptosis induce different changes of kinase signaling in multiple myeloma cells (Logie et al, 2021). On the other hand, in a related study, apoptosis-dependent ferroptosis was found have occured in leukemia cells , suggesting a possible interdependence of the two PCD.…”