Abstract
BackgroundProgesterone receptor membrane component 1 (PGRMC1) is a heme-binding protein inducing dimerization with cytochrome P450, which mediates chemoresistance. Increased PGRMC1 expression is found in multiple types of resistant cancers, but the role of PGRMC1 in the ferroptosis of cancer cells remains unrevealed. Therefore, we examined the role of PGRMC1 in promoting ferroptosis in paclitaxel-tolerant persister cancer cells (PCC).MethodsThe effects of ferroptosis inducers and PGRMC1 gene silencing/overexpression were tested on head and neck cancer (HNC) cell lines and mouse tumor xenograft models. The results were analyzed about cell viability, death, lipid ROS and iron production, mRNA/protein expression and interaction, and lipid assays.ResultsPCC had more free fatty acids, lipid droplets, and fatty acid oxidation (FAO) than their parental cells. PCC was highly sensitive to inhibitors of system xc− cystine/glutamate antiporter (xCT), such as erastin, sulfasalazine, and cyst(e)ine deprivation, but less sensitive to (1S,3R)-RSL3. PGRMC1 silencing in PCC reduced ferroptosis sensitivity by xCT inhibitors, and PGRMC1 overexpression in parental cells increased ferroptosis by xCT inhibitors. Lipid droplets were degraded along with autophagy induction and autophagosome formation by erastin treatment in PCC. Lipophagy was accompanied by increased tubulin detyrosination, which was increased by SIRT1 activation but decreased by SIRT1 inhibition. FAO and lipophagy were also promoted by the interaction between lipid droplets and mitochondria.ConclusionPGRMC1 expression increased FAO and ferroptosis sensitivity from in vivo mice experiments. Our data suggest that PGRMC1 promotes ferroptosis by xCT inhibition in PCC.
Highlights
Progesterone receptor membrane component 1 (PGRMC1) is a heme-binding protein inducing dimeri‐ zation with cytochrome P450, which mediates chemoresistance
Paclitaxel-tolerant persister cancer cells (PCC) had PGRMC1 upregulation related to increased free fatty acids, lipid droplets, and fatty acid oxidation
PGRMC1 expression substantially increased ferroptosis by System xc− cystine/glutamate antiporter (xCT) inhibition via lipophagy and tubulin detyrosination, whereas PGRMC1 silencing decreased ferroptosis: this suggests that PGRMC1 expression promotes ferroptosis in PCC
Summary
Progesterone receptor membrane component 1 (PGRMC1) is a heme-binding protein inducing dimeri‐ zation with cytochrome P450, which mediates chemoresistance. Increased PGRMC1 expression is found in multiple types of resistant cancers, but the role of PGRMC1 in the ferroptosis of cancer cells remains unrevealed. We examined the role of PGRMC1 in promoting ferroptosis in paclitaxel-tolerant persister cancer cells (PCC). Despite the development of various anti-cancer agents, cancer cells can evade effective treatment via some of the ways from pre-existing resistance, de novo mutations, and drug-tolerant persisters [1]. Drug-tolerant persister cancer cells are small surviving fractions evading from chemotherapeutic drugs that cause a significant drawback of conventional or targeted therapy. A slow glowing persister cancer cells are more resistant to anti-cancer drugs [2]. Understanding the resistant mechanisms can lead to incremental innovation for the development of effective anti-cancer strategies. Acquired drug resistance can be overcome by ferroptosis inducers targeting xCT or GPX4, the central regulator of ferroptosis [5, 6]
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