Targeting therapy-resistant lung cancer stem cells via disruption of the AKT/TSPYL5/PTEN positive-feedback loop

In-Gyu Kim,Rae-Kwon Kim,Seo-Yeon Kim,Jei-Ha Lee,Chang-Kyu Heo,Eun-Wie Cho

doi:10.1038/s42003-021-02303-x

Abstract

Cancer stem cells (CSCs) are regarded as essential targets to overcome tumor progression and therapeutic resistance; however, practical targeting approaches are limited. Here, we identify testis-specific Y-like protein 5 (TSPYL5) as an upstream regulator of CSC-associated genes in non-small cell lung cancer cells, and suggest as a therapeutic target for CSC elimination. TSPYL5 elevation is driven by AKT-dependent TSPYL5 phosphorylation at threonine-120 and stabilization via inhibiting its ubiquitination. TSPYL5-pT120 also induces nuclear translocation and functions as a transcriptional activator of CSC-associated genes, ALDH1 and CD44. Also, nuclear TSPYL5 suppresses the transcription of PTEN, a negative regulator of PI3K signaling. TSPYL5-pT120 maintains persistent CSC-like characteristics via transcriptional activation of CSC-associated genes and a positive feedback loop consisting of AKT/TSPYL5/PTEN signaling pathway. Accordingly, elimination of TSPYL5 by inhibiting TSPYL5-pT120 can block aberrant AKT/TSPYL5/PTEN cyclic signaling and TSPYL5-mediated cancer stemness regulation. Our study suggests TSPYL5 be an effective target for therapy-resistant cancer.

Highlights

Cancer stem cells (CSCs) are regarded as essential targets to overcome tumor progression and therapeutic resistance; practical targeting approaches are limited
CD44 binds to hyaluronic acid or osteopontin to maintain a CSC phenotype and promote epithelial-to-mesenchymal transition (EMT), which is required for radiation or drug resistance as well as metastasis in cancer cells[14,15,16,17]
CSC-like properties of these cells were further demonstrated by the increased expression of CSC biomarkers, including ALDH1 (ALDH1A1 and ALDH1A3 isoforms), CD44, SOX-2, and OCT-4 (Fig. 1d and Supplementary Fig. 1b)

Summary

Introduction

Cancer stem cells (CSCs) are regarded as essential targets to overcome tumor progression and therapeutic resistance; practical targeting approaches are limited. We identify testis-specific Y-like protein 5 (TSPYL5) as an upstream regulator of CSC-associated genes in non-small cell lung cancer cells, and suggest as a therapeutic target for CSC elimination. We found that TSPYL5 is associated with γ-radiation resistance in non-small-cell lung cancer (NSCLC) cells through regulation of the PTEN/AKT pathway[27]. It is well known that the PTEN/PI3K/AKT pathway is involved in the acquisition of resistance to EGFR-TKIs28–30, and plays a pivotal role in CSC maintenance[31,32] Based on these findings, we speculate that TSPYL5 may enhance CSC-like properties that promote γ-radiation and drug resistance in cancer cells via the PTEN/AKT signaling pathway.

Methods

Results

Conclusion