Long non-coding RNA GBCDRlnc1 induces chemoresistance of gallbladder cancer cells by activating autophagy

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Abstract

Background

Gallbladder cancer is the most common biliary tract malignancy and not sensitive to chemotherapy. Autophagy is an important factor prolonging the survival of cancer cells under chemotherapeutic stress. We aimed to investigate the role of long non-coding RNAs (lncRNAs) in autophagy and chemoresistance of gallbladder cancer cells.

Methods

We established doxorubicin (Dox)-resistant gallbladder cancer cells and used microarray analysis to compare the expression profiles of lncRNAs in Dox-resistant gallbladder cancer cells and their parental cells. Knockdown or exogenous expression of lncRNA combined with in vitro and in vivo assays were performed to prove the functional significance of lncRNA. The effects of lncRNA on autophagy were assessed by stubRFP-sensGFP-LC3 and western blot. We used RNA pull-down and mass spectrometry analysis to identify the target proteins of lncRNA.

Results

The drug-resistant property of gallbladder cancer cells is related to their enhanced autophagic activity. And we found a lncRNA ENST00000425894 termed gallbladder cancer drug resistance-associated lncRNA1 (GBCDRlnc1) that serves as a critical regulator in gallbladder cancer chemoresistance. Furthermore, we discovered that GBCDRlnc1 is upregulated in gallbladder cancer tissues. Knockdown of GBCDRlnc1, via inhibiting autophagy at initial stage, enhanced the sensitivity of Dox-resistant gallbladder cancer cells to Dox in vitro and in vivo. Mechanically, we identified that GBCDRlnc1 interacts with phosphoglycerate kinase 1 and inhibits its ubiquitination in Dox-resistant gallbladder cancer cells, which leads to the down-regulation of autophagy initiator ATG5-ATG12 conjugate.

Conclusions

Our findings established that the chemoresistant driver GBCDRlnc1 might be a candidate therapeutic target for the treatment of advanced gallbladder cancer.

Electronic supplementary material

The online version of this article (10.1186/s12943-019-1016-0) contains supplementary material, which is available to authorized users.

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Most cited references 29

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Carcinoma of the gallbladder.

Sanjeev Misra, Arun Chaturvedi, Naresh Misra … (2003)

Carcinoma of the gallbladder is the most common malignant tumour of the biliary tract and a particularly high incidence is observed in Chile, Japan, and northern India. The aetiology of this tumour is complex, but there is a strong association with gallstones. Owing to its non-specific symptoms, gallbladder carcinoma is generally diagnosed late in the disease course, but if a patient with gallstones experiences a sudden change of symptoms, then a cancer diagnosis should be considered. Treatment with radical or extended cholecystectomy is potentially curative, although these procedures are only possible in 10-30% of patients. There is no role for cytoreductive surgery in this disease. If a gallbladder carcinoma is discovered via pathological examination of tissue samples, then the patient should be examined further and should have radical surgery if the tumour is found to be T1b or beyond. Additional port-site excision is necessary if the patient has already had their gallbladder removed during laparoscopy; however, patients with an intact gallbladder who are suspected to have gallbladder carcinoma should not undergo laparoscopic cholecystectomy. Patients with advanced inoperable disease should receive palliative treatment; however, the role of chemotherapy and radiation in these patients needs further evaluation.

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Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stress-related apoptosis.

Zhen Ding, Xiao Wang, Ben B. Hui … (2011)

Sorafenib, a potent multikinase inhibitor, has been recognized as the standard systemic treatment for patients with advanced hepatocellular carcinoma (HCC). However, the direct functional mechanism of tumor lethality mediated by sorafenib remains to be fully characterized, and the precise mechanisms of drug resistance are largely unknown. Here, we showed sorafenib induced both apoptosis and autophagy in human HCC cells through a mechanism that involved endoplasmic reticulum (ER) stress and was independent of the MEK1/2-ERK1/2 pathway. Upregulation of IRE1 signals from sorafenib-induced ER stress was critical for the induction of autophagy. Moreover, autophagy activation alleviated the ER stress-induced cell death. Inhibition of autophagy using either pharmacological inhibitors or essential autophagy gene knockdown enhanced cell death in sorafenib treated HCC cell lines. Critically, the combination of sorafenib with the autophagy inhibitor chloroquine produced more pronounced tumor suppression in HCC both in vivo and in vitro. These findings indicated that both ER stress and autophagy were involved in the cell death evoked by sorafenib in HCC cells. The combination of autophagy modulation and molecular targeted therapy is a promising therapeutic strategy in treatment of HCC.

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Phosphoglycerate Kinase 1 Phosphorylates Beclin1 to Induce Autophagy.

Xu Qian, Xinjian Li, Qingsong Cai … (2017)

Autophagy is crucial for maintaining cell homeostasis. However, the precise mechanism underlying autophagy initiation remains to be defined. Here, we demonstrate that glutamine deprivation and hypoxia result in inhibition of mTOR-mediated acetyl-transferase ARD1 S228 phosphorylation, leading to ARD1-dependent phosphoglycerate kinase 1 (PGK1) K388 acetylation and subsequent PGK1-mediated Beclin1 S30 phosphorylation. This phosphorylation enhances ATG14L-associated class III phosphatidylinositol 3-kinase VPS34 activity by increasing the binding of phosphatidylinositol to VPS34. ARD1-dependent PGK1 acetylation and PGK1-mediated Beclin1 S30 phosphorylation are required for glutamine deprivation- and hypoxia-induced autophagy and brain tumorigenesis. Furthermore, PGK1 K388 acetylation levels correlate with Beclin1 S30 phosphorylation levels and poor prognosis in glioblastoma patients. Our study unearths an important mechanism underlying cellular-stress-induced autophagy initiation in which the protein kinase activity of the metabolic enzyme PGK1 plays an instrumental role and reveals the significance of the mutual regulation of autophagy and cell metabolism in maintaining cell homeostasis.

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Author and article information

Contributors

Zhiwei Quan:

ORCID: http://orcid.org/0000-0003-0779-4096

86-139-01647399 , quanzhiwei@xinhuamed.com.cn

Journal

Journal ID (nlm-ta): Mol Cancer

Journal ID (iso-abbrev): Mol. Cancer

Title: Molecular Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-4598

Publication date (Electronic): 5 April 2019

Publication date PMC-release: 5 April 2019

Publication date Collection: 2019

Volume: 18

Electronic Location Identifier: 82

Affiliations

[1 ]ISNI 0000 0004 0368 8293, GRID grid.16821.3c, Department of General Surgery, XinHua Hospital, Shanghai JiaoTong University School of Medicine, ; Shanghai, 200092 China

[2 ]ISNI 0000 0004 0368 8293, GRID grid.16821.3c, Department of Surgery, , Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, ; Shanghai, 200025 China

Author information

Zhiwei Quan http://orcid.org/0000-0003-0779-4096

Article

Publisher ID: 1016

DOI: 10.1186/s12943-019-1016-0

PMC ID: 6449938

PubMed ID: 30953511

SO-VID: af93a987-eb74-4bae-864e-6bea5ff72cfc

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 18 January 2019

Date accepted : 28 March 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81572297

Award ID: 81772515

Award Recipient : Zhiwei Quan

Funded by: Medical Transformation Cross Foundation of Shanghai Jiao Tong University

Award ID: ZH2018QNA49

Award Recipient : Qiang Cai

Funded by: Doctoral Innovation Fund Projects from Shanghai Jiao Tong University School of Medicine

Award ID: BXJ201725

Award Recipient : Qiang Cai

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: lncrna gbcdrlnc1,gallbladder cancer,chemoresistance,autophagy,pgk1

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: lncrna gbcdrlnc1, gallbladder cancer, chemoresistance, autophagy, pgk1

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Long non-coding RNA GBCDRlnc1 induces chemoresistance of gallbladder cancer cells by activating autophagy

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Abstract

Background

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Electronic supplementary material

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Karger: Oncology

Most cited references 29

Carcinoma of the gallbladder.

Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stress-related apoptosis.

Phosphoglycerate Kinase 1 Phosphorylates Beclin1 to Induce Autophagy.

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Cited by 104

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