Table 2 Posttranslational modification of ferroptosis by phosphorylation in cancer
Cancer | Modification | Targets | Enzyme | Biological functions | Ref. |
|---|---|---|---|---|---|
CRC | Phosphorylation | BECN1 | AMPK | AMPK-mediated BECN1 phosphorylation promotes ferroptosis by directly blocking system Xc– activity. | |
CRC | Phosphorylation | Nrf2 | GSK3β | KIF20A was highly expressed in the oxaliplatin-resistant cell lines. Silencing KIF20A enhanced cellular sensitivity to oxaliplatin, and suppressed NUAK1, thereby upregulating the expression of PP1β, down-regulating the phosphorylation of downstream GSK3β to suppressed activation of Nrf2 and the expression of GPX4, and blocked cellular resistance. | |
HCC | Phosphorylation | GPX4 | AKT/CKB | IGF1R activated AKT phosphorylates CKB at T133, reduces metabolic activity of CKB and increases CKB binding to and phosphorylates GPX4 at S104, which prevents HSC70 binding to GPX4, thereby abrogating the GPX4 degradation regulated by chaperone-mediated autophagy, alleviating ferroptosis and promoting tumor growth in mice. | |
HCC | Phosphorylation | RRM2 | - | Elevated RRM2 inhibited ferroptosis. Phosphorylation of RRM2 was maintained at normal levels to block the RRM2-GSS interaction and therefore protected RRM2 and GSS from further proteasome degradation. However, under ferroptotic stress, RRM2 was dephosphorylated at T33, thus the RRM2-GSS interaction was promoted. This resulted in the translocation of RRM2 and GSS to the proteasome for simultaneous degradation. | |
GC | Phosphorylation | eIF2α | - | MESH1 knockdown upregulate ATF3 and ATF4 protein, eIF2α phosphorylation, and induction of ATF3, XBPs, and CHOP mRNA. Concurrent ATF4 knockdown re-sensitizes MESH1-depleted RCC4 cells to ferroptosis. ATF3 induction is abolished by the concurrent knockdown of NADK, implicating a role of NADPH accumulation in the integrative stress response. | |
Breast cancer | Phosphorylation | ACSL4 | PKCβII | PKCβII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis. | |
Breast cancer | Phosphorylation | DDR2 | - | Erastin treatment induces DDR2 upregulation and phosphorylation. EMT-driven DDR2 upregulation in recurrent tumors in maintaining growth advantage but activating YAP/TAZ-mediated ferroptosis susceptibility. | |
TNBC | Phosphorylation | eIF2α | - | Cystine starvation activate GCN2 to increase the phosphorylation of eIF2α, the protein expression of ATF4, and CHAC1. Knockdown of CHAC1 rescued the cystine-starvation-induced ferroptosis. | |
NSCLC | Phosphorylation | YAP | PKA | Inhibition of system XC- increase endogenous glutamate accumulation, by which promotes Ca2+-dependent cAMP production by ADCY10 to stimulate PKA-associated phosphorylation and suppression of GFPT1. Subsequently, YAP is inevitably suppressed and fail to sustain ferritinophagy-triggered transcriptional compensatory of FTH1, leading to a varied labile iron elevation and ferroptosis sensitivity. | |
Osteosarcoma/prostate adenocarcinoma | Phosphorylation | HSPB1 | PKC | Knockdown of HSF1 and HSPB1 enhances erastin-induced ferroptosis, whereas heat shock pretreatment and overexpression of HSPB1 inhibits erastin-induced ferroptosis. PKC-mediated HSPB1 phosphorylation confers protection against ferroptosis. Moreover, inhibition of the HSF1-HSPB1 pathway and HSPB1 phosphorylation increases the anticancer activity of erastin in human xenograft mouse tumor models. |
