PPIP5K2 Facilitates Proliferation and Metastasis of Non-Small Lung Cancer (NSCLC) through AKT Signaling Pathway

TL;DR

This study shows that PPIP5K2 promotes non-small lung cancer growth and spread by activating the AKT/mTOR pathway, suggesting it could be a new treatment target.

Contribution

The study identifies PPIP5K2 as a novel driver of NSCLC progression via AKT/mTOR signaling.

Findings

PPIP5K2 promotes NSCLC cell proliferation in vitro and in vivo.

PPIP5K2 regulates NSCLC metastasis through epithelial-mesenchymal transition (EMT).

PPIP5K2 activates the AKT/mTOR signaling pathway to drive tumorigenesis.

Abstract

Despite significant advancements in the detection and treatment of non-small lung cancer (NSCLC) over the last 20 years, the long-term benefits of treatment are limited due to the development of therapy resistance and distal metastasis. Therefore, the molecular mechanisms underlying NSCLC tumorigenesis must be identified to develop novel therapeutic targets to lessen malignancy and enhance patient outcomes. This study aimed to investigate how Diphosphoinositol Pentakisphosphate Kinase 2 (PPIP5K2) influenced the proliferation and metastasis of NSCLC by modulating AKT/mTOR signaling pathway using functional and mechanistic analyses. Our findings might contribute to the creation of innovative prognostic and therapeutic strategies for NSCLC patients.

Through facilitating DNA homologous recombination repair, PPIP5K2 has been proven to be essential for improving colorectal cancer survival in our previous research. However, its function in the tumorigenesis of NSCLC, the most common cancer and the primary cause of cancer-related death globally, is still unknown. Here, we initially discovered that PPIP5K2 had significant effects on proliferation of NSCLC cells through loss- and gain-of-function assays in vitro and in vivo. Moreover, PPIP5K2 is capable of regulating NSCLC cells metastasis in an EMT-dependent manner. In terms of mechanism exploration, we found that PPIP5K2 knockdown can significantly inhibit the phosphorylation of AKT/mTOR signaling pathway, whereas the overexpression of PPIP5K2 resulted in converse effects. By employing AKT signaling related agonists or antagonists, we further demonstrated that PPIP5K2 regulates NSCLC tumorigenesis partly via the AKT/mTOR pathway. In conclusion, PPIP5K2 plays a key oncogenic role in NSCLC by the activation of the AKT/mTOR signaling axis. It is anticipated that targeting PPIP5K2 might emerge as a viable therapeutic approach for NSCLC patients.

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