Nitrogen permease regulator-like 2 enhances sensitivity to oxaliplatin in colon cancer cells

Liu, Ming‐Na; Liu, Ai‐Yun; Du, Ya-Ju; Pei, Feng‐Hua; Wang, Xin‐Hong; Chen, Jing; Liú, Dan; Hai, Shi

doi:10.3892/mmr.2015.3495

Cited by 5 publications

(5 citation statements)

References 27 publications

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“…Colony formation was impaired in NPRL2 ++/++ cells and this inhibition of colony formation and induction of apoptosis were significantly enhanced with the carboplatin treatment. Our group along with others in different cancers previously reported that NPRL2 enhances sensitivity to chemotherapy and overcomes drug resistance (10,11,31–33). Other studies also have shown that NPRL2 promotes chemoresistance in prostate cancer by activating autophagy (34,35).…”

Section: Discussionmentioning

confidence: 61%

“…However, we recently established the role of TUSC2, another tumor suppressor gene in the same cluster in chromosome 3p21. 31, in activating innate and adaptive immunity. TUSC2 selectively augments natural killer (NK) cells and cytotoxic T lymphocyte (CTL) activity in peripheral blood and the TME, induces a Th1-mediated immune response, and downregulates MDSC and regulatory T cells (Treg) (19).…”

Section: Introductionmentioning

confidence: 99%

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NPRL2 gene therapy induces effective antitumor immunity in KRAS/STK11 mutant anti-PD1 resistant metastatic non-small cell lung cancer (NSCLC) in a humanized mouse model

Meraz,

Majidi,

Song

et al. 2024

Preprint

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NPRL2/TUSC4 is a tumor suppressor gene whose expression is reduced in many cancers including NSCLC. Restoration of NPRL2 expression in cancer cells induces DNA damage which leads to cell cycle arrest and apoptosis. We investigated the antitumor immune responses to NPRL2 gene therapy in aPD1R/ KRAS/STK11mt NSCLC in a humanized mouse model. Humanized mice were generated by transplanting fresh human cord blood derived CD34 stem cells into sub-lethally irradiated NSG mice. Lung metastases were developed from KRAS/STK11mt/aPD1R A549 cells in humanized mice and treated with NPRL2 gene-loaded cationic lipid nanoparticles (DOTAP-NPRL2) with or without pembrolizumab (aPD1). NPRL2 treatment reduced lung metastases significantly, whereas pembrolizumab was ineffective. The antitumor effect was greater in humanized than non-humanized mice suggesting that an immune response contributed to antitumor activity. NPRL2 combined with pembrolizumab was not synergistic in the KRAS/STK11mt/aPD1R tumors but was synergistic in the KRASwt/aPD1S H1299 tumors. Consistent with the A549 humanized mouse model, NPRL2 showed a significantly strong antitumor effect on KRASmt/aPD1R LLC2 syngeneic tumors, whereas aPD1 was ineffective. The antitumor effect of NPRL2 was correlated with increased infiltration of human cytotoxic immune cells and Ag-presenting HLA-DR+ DC, CD11c DC, and downregulation of myeloid and regulatory T cells in the TME. The antitumor effect of NPRL2 was significantly abolished upon in-vivo depletion of CD8 T, macrophages, and CD4 T cells. However, the antitumor effect remained unaffected upon in-vivo depletion of NK cells. A distinct pattern of gene expression profile was found in lung met after NPRL2 treatment in humanized mice. The expression of genes associated with T cell functions, including IFNγ, CD8b, CD7, TNFSF18, ITGA1, GATA3, and TBX21 was significantly increased, whereas the expression of genes associated with negative regulation of T cell functions, including FOXP3, TGFB1, TGFB2, and IL-10RA were strongly inhibited upon NPRL2 treatment. NPRL2 downregulated the expression of T cell co-inhibitory molecules, including CTLA4, ICOS, LAG3, PDCD1, CD274, IDO1, PDCD1LG2, CD47, and KLRB1. Tumors established from NPRL2 stably expressing cells in humanized mice exhibited significantly slower growth compared to controls. TME analysis showed an increased presence of human CD45+, CD3+ T, CD8+ T cells, and HLA-DR+ dendritic cells and a decreased percentage of Treg, CD3+PD1+T cells, MDSC, and CD163+ TAM in NPRL2-expressing tumors. In-vitro, NPRL2 stably expressing cells showed a substantial increase in colony formation inhibition and heightened sensitivity to carboplatin in colony formation, apoptosis, and PARP cleavage assays. Stable expression of NPRL2 resulted in the downregulation of MAPK and AKT-mTOR growth signaling through inhibition of pAKT, pmTOR, pPRAS40, p4E-BP1, and pS6 expression. Taken together, these data suggest that NPRL2 gene therapy induces antitumor activity on KRAS/STK11mt/aPD1R tumors through DC-mediated antigen presentation and cytotoxic immune cell activation.

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Section: Discussionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 99%

NPRL2 gene therapy induces effective antitumor immunity in KRAS/STK11 mutant anti-PD1 resistant metastatic non-small cell lung cancer (NSCLC) in a humanized mouse model

Meraz,

Majidi,

Song

et al. 2024

Preprint

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“…We have explored the role of NPRL2 in drug resistance against L-OHP11 and 5-FU12 on HCT116 cells, showing that NPRL2 enhanced the sensitivity of CRC cells to L-OHP and 5-FU. In the present study, we examined the effects of NPRL2 in combination with L-OHP or 5-FU on CRC in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…However, NPRL2 reportedly played pro-tumor roles in prostate cancer 9. Our previous studies have revealed that NPRL2 acted as a functional tumor suppressor in the CRC cell lines HCT116 and HT29,10 enhanced the sensitivity of HCT116 cells to oxaliplatin11 and 5-ﬂuorouracil,12 and was downregulated at both the blood and tissue levels in CRC patients compared with that in healthy individuals 13…”

Section: Introductionmentioning

confidence: 99%

<p>Nitrogen Permease Regulator-Like-2 Exhibited Anti-Tumor Effects And Enhanced The Sensitivity Of Colorectal Cancer Cells To Oxaliplatin And 5-Fluorouracil</p>

Liu¹,

Jian²,

He³

et al. 2019

OTT

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BackgroundColorectal cancer (CRC) is one of the most common malignant tumors in the world. Our previous study revealed that nitrogen permease regulator-like-2 (NPRL2), a promising anti-tumor gene, was downregulated at both the blood and tissue levels in CRC patients compared with that in healthy individuals.PurposeThis study aims to explore the role of NPRL2 in CRC.MethodsHerein, we constructed NPRL2 overexpression lentivirus vectors and transfected them into HT29 cells. The transfected cells were inoculated subcutaneously into nude mice. Tumor growth, pathology, apoptosis, and the protein expression of caspase-3, caspase-7, Bax, Bcl-2, and phosphorylated protein kinase B (p-Akt) were evaluated. To further explore whether NPRL2 could reduce drug resistance of CRC cells against oxaliplatin (L-OHP) and 5-fluorouracil (5-FU), we constructed a tumor model using HT29 cells. The tumor model was treated with lentiviral particles assembled with vectors encoding NPRL2 and exposed to L-OHP and 5-FU. Tumor growth, pathology, apoptosis, and the protein expression of caspase-3, caspase-7, Bax, Bcl-2, p-Akt, P-glycoprotein (P-gp), and multidrug resistance protein 1 (MRP1) were evaluated.ResultsThe results indicated that in the in vivo CRC xenograft model, NPRL2 reduced the tumor volume and weight and enhanced apoptosis. Our results also confirmed that NPRL2 enhanced the sensitivity of CRC cells to L-OHP and 5-FU. Our studies further demonstrated that NPRL2 exerted anti-tumor and anti-drug resistance effects through the caspase-3, caspase-7, Bax, Bcl-2, Akt, P-gp, and MRP1 pathways.ConclusionOur present work demonstrated that NPRL2 exhibited anti-tumor effects and enhanced the sensitivities of CRC cells to L-OHP and 5-FU through the P-gp and MRP1 pathways.

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“…Based on the level of DNA lesions, the stimulation of DNA damage signaling leads to DNA repair or apoptosis [ 7 ]. Evaluations have revealed that NPRL2 elevates vulnerability to anticancer drugs and apoptosis and we previously showed that NPRL2 improves sensitivity to oxaliplatin in colon cancer cells [ 5 , 8 ]. CPT-11 and oxaliplatin are the most often utilized chemotherapy treatments for CRC [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Nitrogen Permease Regulator Like-2 (NPRL2) Enhances Sensitivity to Irinotecan (CPT-11) in Colon Cancer Cells by Activating the DNA Damage Checkpoint Pathway

Liu

2018

Med Sci Monit

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BackgroundColorectal cancer (CRC) is the third most common cancer worldwide, making it is a serious threat to human health. It is imperative to develop new therapeutics to improve the CRC treatment efficiency. The aim of this study was to investigate the role of NPRL2 in improving sensitivity to CPT-11 in colon cancer cells.Material/MethodsNPRL2 overexpression was established by transfecting the recombinant lentivirus-encoding NPRL2 gene into HCT116 colon cancer cells. Cell proliferation was identified using Cell Counting Kit-8 (CCK8) assay. Cell cycle and apoptosis were examined by flow cytometry. An immunofluorescence staining assay was conducted to examine the expression of γ-H2AX. Wound-healing and Transwell assays were utilized to show cell migration and invasion capability. The expression of apoptosis-related proteins (cleaved caspase-3, caspase-9, cleaved PARP, BAX, and Bcl-2), invasion-related proteins (MMP2, MMP9, p-PI3K, and p-AKT), and DNA damage checkpoint pathway proteins (p-ATM, p-Chk2, Cdc25C, Cdc2, and Cyclin B1) were quantified by Western blotting.ResultsA CCK8 assay revealed that the overexpression of NPRL2 improved the sensitivity of CPT-11 in HCT116 cells (P<0.05). Functionally, NPRL2 overexpression elevated the sensitivity of CPT-11 by preventing colon cancer cell proliferation, cell movement, and invasion, and promoting cell apoptosis and G2/M cell cycle arrest. Mechanistically, NPRL2 overexpression enhanced CPT-11 sensitivity by activating the DNA damage checkpoint pathway.ConclusionsNPRL2 overexpression enhances sensitivity to CPT-11 treatment in colon cancer cells, and it may serve as a molecular therapeutic agent to treat patients with CRC.

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Nitrogen permease regulator-like 2 enhances sensitivity to oxaliplatin in colon cancer cells

Cited by 5 publications

References 27 publications

NPRL2 gene therapy induces effective antitumor immunity in KRAS/STK11 mutant anti-PD1 resistant metastatic non-small cell lung cancer (NSCLC) in a humanized mouse model

NPRL2 gene therapy induces effective antitumor immunity in KRAS/STK11 mutant anti-PD1 resistant metastatic non-small cell lung cancer (NSCLC) in a humanized mouse model

<p>Nitrogen Permease Regulator-Like-2 Exhibited Anti-Tumor Effects And Enhanced The Sensitivity Of Colorectal Cancer Cells To Oxaliplatin And 5-Fluorouracil</p>

Overexpression of Nitrogen Permease Regulator Like-2 (NPRL2) Enhances Sensitivity to Irinotecan (CPT-11) in Colon Cancer Cells by Activating the DNA Damage Checkpoint Pathway

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