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NDAT Targets PI3K-Mediated PD-L1 Upregulation to Reduce Proliferation in Gefitinib-Resistant Colorectal Cancer

The property of drug-resistance may attenuate clinical therapy in cancer cells, such as chemoresistance to gefitinib in colon cancer cells. In previous studies, overexpression of PD-L1 causes proliferation and metastasis in cancer cells; therefore, the PD-L1 pathway allows tumor cells to exert an ad...

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Autores principales: Huang, Tung-Yung, Chang, Tung-Cheng, Chin, Yu-Tang, Pan, Yi-Shin, Chang, Wong-Jin, Liu, Feng-Cheng, Hastuti, Ema Dwi, Chiu, Shih-Jiuan, Wang, Shwu-Huey, Changou, Chun A., Li, Zi-Lin, Chen, Yi-Ru, Chu, Hung-Ru, Shih, Ya-Jung, Cheng, R. Holland, Wu, Alexander, Lin, Hung-Yun, Wang, Kuan, Whang-Peng, Jacqueline, Mousa, Shaker A, Davis, Paul J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464180/
https://www.ncbi.nlm.nih.gov/pubmed/32756527
http://dx.doi.org/10.3390/cells9081830
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author Huang, Tung-Yung
Chang, Tung-Cheng
Chin, Yu-Tang
Pan, Yi-Shin
Chang, Wong-Jin
Liu, Feng-Cheng
Hastuti, Ema Dwi
Chiu, Shih-Jiuan
Wang, Shwu-Huey
Changou, Chun A.
Li, Zi-Lin
Chen, Yi-Ru
Chu, Hung-Ru
Shih, Ya-Jung
Cheng, R. Holland
Wu, Alexander
Lin, Hung-Yun
Wang, Kuan
Whang-Peng, Jacqueline
Mousa, Shaker A
Davis, Paul J.
author_facet Huang, Tung-Yung
Chang, Tung-Cheng
Chin, Yu-Tang
Pan, Yi-Shin
Chang, Wong-Jin
Liu, Feng-Cheng
Hastuti, Ema Dwi
Chiu, Shih-Jiuan
Wang, Shwu-Huey
Changou, Chun A.
Li, Zi-Lin
Chen, Yi-Ru
Chu, Hung-Ru
Shih, Ya-Jung
Cheng, R. Holland
Wu, Alexander
Lin, Hung-Yun
Wang, Kuan
Whang-Peng, Jacqueline
Mousa, Shaker A
Davis, Paul J.
author_sort Huang, Tung-Yung
collection PubMed
description The property of drug-resistance may attenuate clinical therapy in cancer cells, such as chemoresistance to gefitinib in colon cancer cells. In previous studies, overexpression of PD-L1 causes proliferation and metastasis in cancer cells; therefore, the PD-L1 pathway allows tumor cells to exert an adaptive resistance mechanism in vivo. Nano-diamino-tetrac (NDAT) has been shown to enhance the anti-proliferative effect induced by first-line chemotherapy in various types of cancer, including colorectal cancer (CRC). In this work, we attempted to explore whether NDAT could enhance the anti-proliferative effect of gefitinib in CRC and clarified the mechanism of their interaction. The MTT assay was utilized to detect a reduction in cell proliferation in four primary culture tumor cells treated with gefitinib or NDAT. The gene expression of PD-L1 and other tumor growth-related molecules were quantified by quantitative polymerase chain reaction (qPCR). Furthermore, the identification of PI3K and PD-L1 in treated CRC cells were detected by western blotting analysis. PD-L1 presentation in HCT116 xenograft tumors was characterized by specialized immunohistochemistry (IHC) and the hematoxylin and eosin stain (H&E stain). The correlations between the change in PD-L1 expression and tumorigenic characteristics were also analyzed. (3) The PD-L1 was highly expressed in Colo_160224 rather than in the other three primary CRC cells and HCT-116 cells. Moreover, the PD-L1 expression was decreased by gefitinib (1 µM and 10 µM) in two cells (Colo_150624 and 160426), but 10 µM gefitinib stimulated PD-L1 expression in gefitinib-resistant primary CRC Colo_160224 cells. Inactivated PI3K reduced PD-L1 expression and proliferation in CRC Colo_160224 cells. Gefitinib didn’t inhibit PD-L1 expression and PI3K activation in gefitinib-resistant Colo_160224 cells. However, NDAT inhibited PI3K activation as well as PD-L1 accumulation in gefitinib-resistant Colo_160224 cells. The combined treatment of NDAT and gefitinib inhibited pPI3K and PD-L1 expression and cell proliferation. Additionally, NDAT reduced PD-L1 accumulation and tumor growth in the HCT116 (K-RAS mutant) xenograft experiment. (4) Gefitinib might suppress PD-L1 expression but did not inhibit proliferation through PI3K in gefitinib-resistant primary CRC cells. However, NDAT not only down-regulated PD-L1 expression via blocking PI3K activation but also inhibited cell proliferation in gefitinib-resistant CRCs.
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spelling pubmed-74641802020-09-04 NDAT Targets PI3K-Mediated PD-L1 Upregulation to Reduce Proliferation in Gefitinib-Resistant Colorectal Cancer Huang, Tung-Yung Chang, Tung-Cheng Chin, Yu-Tang Pan, Yi-Shin Chang, Wong-Jin Liu, Feng-Cheng Hastuti, Ema Dwi Chiu, Shih-Jiuan Wang, Shwu-Huey Changou, Chun A. Li, Zi-Lin Chen, Yi-Ru Chu, Hung-Ru Shih, Ya-Jung Cheng, R. Holland Wu, Alexander Lin, Hung-Yun Wang, Kuan Whang-Peng, Jacqueline Mousa, Shaker A Davis, Paul J. Cells Article The property of drug-resistance may attenuate clinical therapy in cancer cells, such as chemoresistance to gefitinib in colon cancer cells. In previous studies, overexpression of PD-L1 causes proliferation and metastasis in cancer cells; therefore, the PD-L1 pathway allows tumor cells to exert an adaptive resistance mechanism in vivo. Nano-diamino-tetrac (NDAT) has been shown to enhance the anti-proliferative effect induced by first-line chemotherapy in various types of cancer, including colorectal cancer (CRC). In this work, we attempted to explore whether NDAT could enhance the anti-proliferative effect of gefitinib in CRC and clarified the mechanism of their interaction. The MTT assay was utilized to detect a reduction in cell proliferation in four primary culture tumor cells treated with gefitinib or NDAT. The gene expression of PD-L1 and other tumor growth-related molecules were quantified by quantitative polymerase chain reaction (qPCR). Furthermore, the identification of PI3K and PD-L1 in treated CRC cells were detected by western blotting analysis. PD-L1 presentation in HCT116 xenograft tumors was characterized by specialized immunohistochemistry (IHC) and the hematoxylin and eosin stain (H&E stain). The correlations between the change in PD-L1 expression and tumorigenic characteristics were also analyzed. (3) The PD-L1 was highly expressed in Colo_160224 rather than in the other three primary CRC cells and HCT-116 cells. Moreover, the PD-L1 expression was decreased by gefitinib (1 µM and 10 µM) in two cells (Colo_150624 and 160426), but 10 µM gefitinib stimulated PD-L1 expression in gefitinib-resistant primary CRC Colo_160224 cells. Inactivated PI3K reduced PD-L1 expression and proliferation in CRC Colo_160224 cells. Gefitinib didn’t inhibit PD-L1 expression and PI3K activation in gefitinib-resistant Colo_160224 cells. However, NDAT inhibited PI3K activation as well as PD-L1 accumulation in gefitinib-resistant Colo_160224 cells. The combined treatment of NDAT and gefitinib inhibited pPI3K and PD-L1 expression and cell proliferation. Additionally, NDAT reduced PD-L1 accumulation and tumor growth in the HCT116 (K-RAS mutant) xenograft experiment. (4) Gefitinib might suppress PD-L1 expression but did not inhibit proliferation through PI3K in gefitinib-resistant primary CRC cells. However, NDAT not only down-regulated PD-L1 expression via blocking PI3K activation but also inhibited cell proliferation in gefitinib-resistant CRCs. MDPI 2020-08-03 /pmc/articles/PMC7464180/ /pubmed/32756527 http://dx.doi.org/10.3390/cells9081830 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Huang, Tung-Yung
Chang, Tung-Cheng
Chin, Yu-Tang
Pan, Yi-Shin
Chang, Wong-Jin
Liu, Feng-Cheng
Hastuti, Ema Dwi
Chiu, Shih-Jiuan
Wang, Shwu-Huey
Changou, Chun A.
Li, Zi-Lin
Chen, Yi-Ru
Chu, Hung-Ru
Shih, Ya-Jung
Cheng, R. Holland
Wu, Alexander
Lin, Hung-Yun
Wang, Kuan
Whang-Peng, Jacqueline
Mousa, Shaker A
Davis, Paul J.
NDAT Targets PI3K-Mediated PD-L1 Upregulation to Reduce Proliferation in Gefitinib-Resistant Colorectal Cancer
title NDAT Targets PI3K-Mediated PD-L1 Upregulation to Reduce Proliferation in Gefitinib-Resistant Colorectal Cancer
title_full NDAT Targets PI3K-Mediated PD-L1 Upregulation to Reduce Proliferation in Gefitinib-Resistant Colorectal Cancer
title_fullStr NDAT Targets PI3K-Mediated PD-L1 Upregulation to Reduce Proliferation in Gefitinib-Resistant Colorectal Cancer
title_full_unstemmed NDAT Targets PI3K-Mediated PD-L1 Upregulation to Reduce Proliferation in Gefitinib-Resistant Colorectal Cancer
title_short NDAT Targets PI3K-Mediated PD-L1 Upregulation to Reduce Proliferation in Gefitinib-Resistant Colorectal Cancer
title_sort ndat targets pi3k-mediated pd-l1 upregulation to reduce proliferation in gefitinib-resistant colorectal cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464180/
https://www.ncbi.nlm.nih.gov/pubmed/32756527
http://dx.doi.org/10.3390/cells9081830
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