Transcriptomic Profiling Reveals AKR1C1 and AKR1C3 Mediate Cisplatin Resistance in Signet Ring Cell Gastric Carcinoma via Autophagic Cell Death

Signet ring cell gastric carcinoma (SRCGC) is a lethal malignancy that has developed drug resistance to cisplatin therapies. The aim of this study was to characterize the acquisition of the cisplatin-resistance SRCGC cell line (KATO/DDP cells) and to understand the molecular mechanisms underlying ci...

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Autores principales:	Nang Lae Lae Phoo, Pornngarm Dejkriengkraikul, Patompong Khaw-On, Supachai Yodkeeree
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	signet ring cell gastric carcinoma RNA sequencing aldoketoreductase autophagy drug resistance Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/1f459c53bcea4ac2847f929eb68f395c
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spelling	oai:doaj.org-article:1f459c53bcea4ac2847f929eb68f395c2021-11-25T17:57:23ZTranscriptomic Profiling Reveals AKR1C1 and AKR1C3 Mediate Cisplatin Resistance in Signet Ring Cell Gastric Carcinoma via Autophagic Cell Death10.3390/ijms2222125121422-00671661-6596https://doaj.org/article/1f459c53bcea4ac2847f929eb68f395c2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12512https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Signet ring cell gastric carcinoma (SRCGC) is a lethal malignancy that has developed drug resistance to cisplatin therapies. The aim of this study was to characterize the acquisition of the cisplatin-resistance SRCGC cell line (KATO/DDP cells) and to understand the molecular mechanisms underlying cisplatin resistance. Transcriptomic and bioinformatic analyses were used to identify the candidate gene. This was confirmed by qPCR and Western blot. Aldoketoreductase1C1 and 1C3 (AKR1C1 and AKR1C3) were the most promising molecules in KATO/DDP cells. A specific inhibitor of AKR1C1 (5PBSA) and AKR1C3 (ASP9521) was used to enhance cisplatin-induced KATO/DPP cell death. Although cisplatin alone induced KATO/DDP apoptosis, a combination treatment of cisplatin and the AKR1C inhibitors had no influence on percent cell apoptosis. In conjunction with the autophagy inhibitor, 3MA, attenuated the effects of 5PBSA or ASP9521 to enhance cisplatin-induced cell death. These results indicated that AKR1C1 and 1C3 regulated cisplatin-induced KATO/DDP cell death via autophagy. Moreover, cisplatin in combination with AKR1C inhibitors and N-acetyl cysteine increased KATO/DDP cells’ viability when compared with a combination treatment of cisplatin and the inhibitors. Taken together, our results suggested that AKR1C1 and 1C3 play a crucial role in cisplatin resistance of SRCGC by regulating redox-dependent autophagy.Nang Lae Lae PhooPornngarm DejkriengkraikulPatompong Khaw-OnSupachai YodkeereeMDPI AGarticlesignet ring cell gastric carcinomaRNA sequencingaldoketoreductaseautophagydrug resistanceBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12512, p 12512 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	signet ring cell gastric carcinoma RNA sequencing aldoketoreductase autophagy drug resistance Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	signet ring cell gastric carcinoma RNA sequencing aldoketoreductase autophagy drug resistance Biology (General) QH301-705.5 Chemistry QD1-999 Nang Lae Lae Phoo Pornngarm Dejkriengkraikul Patompong Khaw-On Supachai Yodkeeree Transcriptomic Profiling Reveals AKR1C1 and AKR1C3 Mediate Cisplatin Resistance in Signet Ring Cell Gastric Carcinoma via Autophagic Cell Death
description	Signet ring cell gastric carcinoma (SRCGC) is a lethal malignancy that has developed drug resistance to cisplatin therapies. The aim of this study was to characterize the acquisition of the cisplatin-resistance SRCGC cell line (KATO/DDP cells) and to understand the molecular mechanisms underlying cisplatin resistance. Transcriptomic and bioinformatic analyses were used to identify the candidate gene. This was confirmed by qPCR and Western blot. Aldoketoreductase1C1 and 1C3 (AKR1C1 and AKR1C3) were the most promising molecules in KATO/DDP cells. A specific inhibitor of AKR1C1 (5PBSA) and AKR1C3 (ASP9521) was used to enhance cisplatin-induced KATO/DPP cell death. Although cisplatin alone induced KATO/DDP apoptosis, a combination treatment of cisplatin and the AKR1C inhibitors had no influence on percent cell apoptosis. In conjunction with the autophagy inhibitor, 3MA, attenuated the effects of 5PBSA or ASP9521 to enhance cisplatin-induced cell death. These results indicated that AKR1C1 and 1C3 regulated cisplatin-induced KATO/DDP cell death via autophagy. Moreover, cisplatin in combination with AKR1C inhibitors and N-acetyl cysteine increased KATO/DDP cells’ viability when compared with a combination treatment of cisplatin and the inhibitors. Taken together, our results suggested that AKR1C1 and 1C3 play a crucial role in cisplatin resistance of SRCGC by regulating redox-dependent autophagy.
format	article
author	Nang Lae Lae Phoo Pornngarm Dejkriengkraikul Patompong Khaw-On Supachai Yodkeeree
author_facet	Nang Lae Lae Phoo Pornngarm Dejkriengkraikul Patompong Khaw-On Supachai Yodkeeree
author_sort	Nang Lae Lae Phoo
title	Transcriptomic Profiling Reveals AKR1C1 and AKR1C3 Mediate Cisplatin Resistance in Signet Ring Cell Gastric Carcinoma via Autophagic Cell Death
title_short	Transcriptomic Profiling Reveals AKR1C1 and AKR1C3 Mediate Cisplatin Resistance in Signet Ring Cell Gastric Carcinoma via Autophagic Cell Death
title_full	Transcriptomic Profiling Reveals AKR1C1 and AKR1C3 Mediate Cisplatin Resistance in Signet Ring Cell Gastric Carcinoma via Autophagic Cell Death
title_fullStr	Transcriptomic Profiling Reveals AKR1C1 and AKR1C3 Mediate Cisplatin Resistance in Signet Ring Cell Gastric Carcinoma via Autophagic Cell Death
title_full_unstemmed	Transcriptomic Profiling Reveals AKR1C1 and AKR1C3 Mediate Cisplatin Resistance in Signet Ring Cell Gastric Carcinoma via Autophagic Cell Death
title_sort	transcriptomic profiling reveals akr1c1 and akr1c3 mediate cisplatin resistance in signet ring cell gastric carcinoma via autophagic cell death
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/1f459c53bcea4ac2847f929eb68f395c
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_version_	1718411788596281344

Transcriptomic Profiling Reveals AKR1C1 and AKR1C3 Mediate Cisplatin Resistance in Signet Ring Cell Gastric Carcinoma via Autophagic Cell Death

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