Stomatin-like protein 2 promotes tumor cell survival by activating the JAK2-STAT3-PIM1 pathway, suggesting a novel therapy in CRC Journal Article
| Authors: | Liu, Q.; Li, A.; Wang, L.; He, W.; Zhao, L.; Wu, C.; Lu, S.; Ye, X.; Zhao, H.; Shen, X.; Xiao, X.; Liu, Z. |
| Article Title: | Stomatin-like protein 2 promotes tumor cell survival by activating the JAK2-STAT3-PIM1 pathway, suggesting a novel therapy in CRC |
| Abstract: | Despite intensive efforts, a considerable proportion of colorectal cancer (CRC) patients develop local recurrence and distant metastasis. Stomatin-like protein 2 (SLP-2), a member of the highly conserved stomatin superfamily, is upregulated across cancer types. However, the biological and functional roles of SLP-2 remain elusive in CRC. Here, we report that high SLP-2 expression was found in CRC tissues and was linked to tumor progression and tumor cell differentiation. Additionally, high SLP-2 expression correlated with poor overall survival (OS) in CRC patients (p < 0.001). SLP-2 knockout (SLP-2KO), generated by CRISPR/Cas9, reduced cell growth, migration, and invasion; induced apoptosis in CRC cells; and reduced tumor xenograft growth in vivo. A 181-compound library screening showed that SLP-2KO produced resistance to JAK2 inhibitors (NVP-BSK805 and TG-101348) and a PIM1 inhibitor (SGI-1776), revealing that the JAK2-STAT3-PIM1 oncogenic pathway was potentially controlled by SLP-2 in CRC. In vitro and in vivo, TG-101348 combined with SGI-1776 was synergistic in CRC (combination index [CI] < 1). Overall, our findings suggest that SLP-2 controls the JAK2-STAT3-PIM1 oncogenic pathway, offering a rationale for a novel therapeutic strategy with combined SGI-1776 and TG-101348 in CRC. Additionally, SLP-2 may be a prognostic marker and biomarker for sensitivity to JAK2 and PIM1 inhibitors. © 2020 The Authors Liu and colleagues show that enhanced SLP-2 expression correlates with tumor progression in CRC. SLP-2 knockout by CRISPR/Cas9 inhibits CRC cell growth. PIM1i SGI-1776 and JAK2i TG-101348 are successfully identified as SLP-2-linked drugs after compound library screening. Co-treatment with the two drugs produces synergistic effect, which provides a promising therapy in CRC. © 2020 The Authors |
| Keywords: | colorectal cancer; stat3; jak2; pim1; stomatin-like protein 2 |
| Journal Title: | Molecular Therapy - Oncolytics |
| Volume: | 17 |
| ISSN: | 2372-7705 |
| Publisher: | Cell Press |
| Date Published: | 2020-06-26 |
| Start Page: | 169 |
| End Page: | 179 |
| Language: | English |
| DOI: | 10.1016/j.omto.2020.03.010 |
| PROVIDER: | scopus |
| PMCID: | PMC7177985 |
| PUBMED: | 32346607 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 May 2020 -- Source: Scopus |
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