PPA1 Promotes Breast Cancer Proliferation and Metastasis Through PI3K/AKT/GSK3β Signaling Pathway

Abstract

Breast cancer is the most common malignancy among women. Inorganic pyrophosphatase 1 (PPA1) is a multifunctional protein involved in the development of several tumors. However, the role of PPA1 in breast cancer progression remains unclear. In this study, we found that PPA1 was highly expressed in breast cancer compared to its levels in normal breast tissue and that it was correlated with breast cancer clinicopathological characteristics, as well as poor survival in breast cancer patients. Silencing PPA1 restrained breast cancer proliferation and metastasis by regulating Slug-mediated epithelial-mesenchymal transition (EMT). Opposite results were observed following PPA1 overexpression. In addition, investigation of the underlying mechanism demonstrated that PPA1 ablation led to decrease phosphatidylinositol 3 kinase (PI3K) phosphorylation levels and attenuate phosphorylated AKT and glycogen synthase kinase-3 β (GSK3β), while ectopic PPA1 expression had the opposite effects. Moreover, PI3K inhibitors suppress the signaling pathways mediating the effects of PPA1 on breast cancer, resulting in tumor growth and metastasis suppression in vitro and in vivo. In summary, our results verify that PPA1 can act as an activator of PI3K/AKT/GSK3β/Slug-mediated breast cancer progression and that it is a potential therapeutic target for the inhibition of tumor progression.

Metabolomics and integrated network pharmacology analysis reveal SNKAF decoction suppresses cell proliferation and induced cell apoptisis in hepatocellular carcinoma via PI3K/Akt/P53/FoxO signaling axis

“…This resulted in the conformational variations at the PI3K receptor and the follow-up recruitment phosphorylation. Following activation, PI3k induced the activation of a core signaling kinase Akt, which controls some downstream effector molecules like glycogen synthase kinase-3β (GSK3β), driving protein and lipid synthesis, and cell development [ 51 , 52 ]. It also induced the activation of the forkhead box O (FOXO) family, which participates in various cellular physiological processes and regulates cell proliferation, cell cycle [ 53 , 54 ].…”

PPA1, an energy metabolism initiator, plays an important role in the progression of malignant tumors

“…The effect of PPA1 on JNK dephosphorylation also induces type I collagen synthesis and stimulates calcification of osteoblasts (38). Furthermore, PPA1 has been shown to play a vital role in mediating tumor proliferation, apoptosis, and metastasis in a JNK activation-dependent or -independent manner; this is discussed in detail below (13,14,17).…”

“…The phosphatidylinositol 3-kinase (PI3K) and its downstream molecule AKT serine/threonine kinase (AKT), have been shown to be closely associated with tumor EMT, and activation of PI3K/AKT leads to the inhibition of epithelial characteristics and expression of mesenchymal proteins (45,46). Guo et al found that PPA1 acts as an activator of the PI3K/AKT/ GSK-3b pathway and participates in the development of EMT induced by transcription factor Slug, thereby promoting breast cancer proliferation and metastasis (17). However, PPA1 is not directly upstream of PI3K, and their molecular interactors have not yet been reported.…”

“…However, PPA1 is not directly upstream of PI3K, and their molecular interactors have not yet been reported. Elevated expression of p-PI3K (Tyr458) promotes phosphorylation of AKT (Ser473) and GSK-3b (Ser9) (17). Phosphorylated GSK-3b is degraded, releasing snail and bcatenin, which enter the nucleus to inhibit the transcriptional activity of E-cadherin (17,47).…”

“…PPA1 differential expression in normal tissues and corresponding malignant tumors indicates its potential as a molecular target for screening, diagnosing, and treating malignancies as well as predicting patient prognosis. Further studies have revealed that PPA1 is positively correlated with the progression of various malignant tumors as a result of its ability to facilitate tumor proliferation, suppress tumor apoptosis (12)(13)(14), and promote tumor metastasis by participating in epithelial-mesenchymal transition (EMT)-related signaling pathways (8,(15)(16)(17). In addition, a new human PPase, phospho-lysine phosphohistidine inorganic pyrophosphate phosphatase (LHPPase), has been cloned, and a significant increase of this protein was found to be associated with hyperthyroidism, while a decrease was observed in thyroid tumors (18).…”