Targeting SPHK1/PBX1 Axis Induced Cell Cycle Arrest in Non-Small Cell Lung Cancer

Abstract

Non-small cell lung cancer (NSCLC) accounts for 85~90% of lung cancer cases, with a poor prognosis and a low 5-year survival rate. Sphingosine kinase-1 (SPHK1), a key enzyme in regulating sphingolipid metabolism, has been reported to be involved in the development of NSCLC, although the underlying mechanism remains unclear. In the present study, we demonstrated the abnormal signature of SPHK1 in NSCLC lesions and cell lines of lung cancers with a potential tumorigenic role in cell cycle regulation. Functionally, ectopic Pre-B cell leukemia homeobox-1 (PBX1) was capable of restoring the arrested G1 phase induced by SPHK1 knockdown. However, exogenous sphingosine-1-phosphate (S1P) supply had little impact on the cell cycle arrest by PBX1 silence. Furthermore, S1P receptor S1PR3 was revealed as a specific switch to transport the extracellular S1P signal into cells, and subsequently activated PBX1 to regulate cell cycle progression. In addition, Akt signaling partially participated in the SPHK1/S1PR3/PBX1 axis to regulate the cell cycle, and the Akt inhibitor significantly decreased PBX1 expression and induced G1 arrest. Targeting SPHK1 with PF-543 significantly inhibited the cell cycle and tumor growth in preclinical xenograft tumor models of NSCLC. Taken together, our findings exhibit the vital role of the SPHK1/S1PR3/PBX1 axis in regulating the cell cycle of NSCLC, and targeting SPHK1 may develop a therapeutic effect in tumor treatment.

PBX1: a TALE of two seasons—key roles during development and in cancer

“…In non-small cell lung cancer PBX1 was recently shown to inhibit tumor growth; in patients' tissues it is indeed downregulated through binding to the ubiquitin ligase TRIM6, which drives PBX1 proteasomal degradation (Sun et al, 2023). However, this is in contrast with a previous report demonstrating a positive role of PBX1 in cell cycle progression (Lin et al, 2022). Contradictory roles of PBX1 are also present in the framework of gastric cancer.…”

“…Sexual developmental defects; CAKUTHED (Mary et al, 2022) Endometrial Carcinoma: Tumor suppressor (Guo et al, 2023) Ovarian Cancer: Oncogene (Park et al, 2008), chemoresistance (Jung et al, 2016) Prostate Cancer: Proliferation (Kikugawa et al, 2006;Liu et al, 2019b) Renal Clear Cell Carcinoma: Cell proliferation via JAK2/STAT3 signaling (Wei et al, 2018) Bladder Cancer: Cell growth, invasion, EMT (Zhao et al, 2022) Gastrointestinal system/ digestive tract Gut aplasia in Pbx1 −/− mice (Selleri et al, 2001) Gastric Carcinoma: potential oncogene (upregulation of miR650 and EMT) (Liu et al, 2021); potential tumor suppressor (upregulation of its PBXIP1 inhibitor) (He et al, 2017) Colorectal Cancer: Metastasis inhibition (Dai et al, 2023) Mouse model of hepatocellular carcinoma: tumor suppressor (upregulation of its PBXIP1 inhibitor) (Xu et al, 2013) Pancreas and pancreatic islands development (Kim et al, 2002) Diabetes mellitus (suggested) (Kim et al, 2002) Lung Lungs development (Li et al, 2014) Non-Small Cell Lung Cancer: Proliferation promotion (Lin et al, 2022) or tumor suppression (Sun et al, 2023) Lymphangioleiomyomatosis: cell survival by inducing expression of antiapoptotic genes (Olatoke et al, 2023) Lung hypoplasia (Mary et al, 2022) Brain Differentiation of olfactory bulb, mesencephalic and midbrain dopaminergic neurons (Sgadò et al, 2012;Remesal et al, 2020); hindbrain segmentation through control of RA synthesis (Vitobello et al, 2011) Brain cancer. Neuroblastoma: higher expression levels in the initial tumor samples compared with responders (Veselska et al, 2019); Glioma: tumor suppressor role) (van Vuurden et al, 2014) Parkinson: reduced levels in dopaminergic neurons (Villaescusa et al, 2016) Other ectoderm derivatives Epithelial cells: Corneal morphogenesis (Murphy et al, 2010); modulation of body-site-specific epidermal barrier (seen with Pbx1 epidermal-specific null mice), auditory sensory epithelium (Li et al, 2020b) Oral squamous cell carcinoma: Oncogene…”