TPI1 activates the PI3K/AKT/mTOR signaling pathway to induce breast cancer progression by stabilizing CDCA5

Abstract

Background Triosephosphate isomerase 1 (TPI1), as a key glycolytic enzyme, is upregulated in multiple cancers. However, expression profile and regulatory mechanism of TPI1 in breast cancer (BRCA) remain mysterious. Methods Western blotting and immunohistochemistry (IHC) assays were used to investigate the expression of TPI1 in BRCA specimens and cell lines. TPI1 correlation with the clinicopathological characteristics and prognosis of 362 BRCA patients was analyzed using a tissue microarray. Overexpression and knockdown function experiments in cells and mice models were performed to elucidate the function and mechanisms of TPI1-induced BRCA progression. Related molecular mechanisms were clarified using co-IP, IF, mass spectrometric analysis, and ubiquitination assay. Results We have found TPI1 is highly expressed in BRCA tissue and cell lines, acting as an independent indicator for prognosis in BRCA patients. TPI1 promotes BRCA cell glycolysis, proliferation and metastasis in vitro and in vivo. Mechanistically, TPI1 activates phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway to regulate epithelial–mesenchymal transformation (EMT) and aerobic glycolysis, which is positively mediated by cell division cycle associated 5 (CDCA5). Moreover, TPI1 interacts with sequestosome-1 (SQSTM1)/P62, and P62 decreases the protein expression of TPI1 by promoting its ubiquitination in MDA-MB-231 cells. Conclusions TPI1 promotes BRCA progression by stabilizing CDCA5, which then activates the PI3K/AKT/mTOR pathway. P62 promotes ubiquitin-dependent proteasome degradation of TPI1. Collectively, TPI1 promotes tumor development and progression, which may serve as a therapeutic target for BRCA.

CDCA5 promotes the progression of breast cancer and serves as a potential prognostic biomarker

“…CDCA5 is aberrantly expressed in various types of cancer, such as hepatocellular carcinoma (35)(36)(37), bladder cancer (38), prostate cancer (39) and renal clear cell carcinoma (40), rendering it a potentially important prognostic marker and potential therapeutic target for cancer patients. However, only a limited number of studies (41)(42)(43) to date have investigated the expression and function of CDCA5 in BRCA.…”

Newly discovered roles of triosephosphate isomerase including functions within the nucleus

“…These data support the conclusion that it is loss of stability and lowered TPI levels ( affecting all TPI functions ) that underlie the disease and open up the possibility that loss of non-glycolytic functions of TPI may contribute to the disease, especially within the neuromuscular system. Indeed, several moonlighting roles have been identified, but the catalytic dependence of these roles is unknown (Daniel et al 2021 ; Jin et al 2022 ; Liu et al 2022 ; Rodriguez-Bolanos and Perez-Montfort 2019 ; Zhang et al 2021 ).…”

“…In Zhang et al ( 2021 ), TPI was found to be regulated through an axis involving mTORC1 and cyclin-dependent kinase 2 (CDK2), where TPI phosphorylation by CDK2 at serine 80 (referred to as Ser117 in the paper referencing a predicted long TPI isoform) resulted in the translocation of TPI to the nucleus. Interestingly, another recent publication further highlighted the importance of mTORC1 in relation to TPI function, where it was shown that TPI promotes tumor growth and migration through an association with cell division cycle associated 5 (CDCA5) which led to the activation of phosphatidylinositol-3-kinase (PI3K) and subsequent activation of the protein kinase B (Akt/PKB) and mTORC1 pathways (Jin et al 2022 ). These two manuscripts suggest that TPI is both regulated by the mTORC1 pathway and that TPI can itself regulate the mTORC1 pathway, at least in cancer.…”

“…The mechanisms and directionality governing the interaction between TPI and mTORC1 must be better investigated to understand this pathway, and studies should extend outside of the context of cancer so that the role of these interactions can be assessed in normal physiology. Aside from mTORC1 signaling, it was also recently reported that TPI protein is regulated by p62 (Jin et al 2022 ). This is a novel and important finding when taken in the context of TPI deficiency, considering that p62 is known to play a role in protein degradation (Chen et al 2020 ).…”

“…Does TPI have nuclear and/or non-catalytic functions? Several intriguing publications suggest TPI may have several functions independent of glycolysis and possibly independent of isomerase activity (Daniel et al 2021 ; Jin et al 2022 ; Liu et al 2022 ; Rodriguez-Bolanos and Perez-Montfort 2019 ; Roland et al 2015 , 2013 ; Zhang et al 2021 ). An overview of the structure of TPI with pertinent residues labeled can be found in Fig.…”