Stress and interferon signalling-mediated apoptosis contributes to pleiotropic anticancer responses induced by targeting NGLY1

Ashwini Zolekar, Victor J.T. Lin, Nigam M. Mishra, Yin Ying Ho, Hamed S. Hayatshahi, Abhishek Parab, Rohit Sampat, Xiaoyan Liao, Peter Hoffmann, Jin Liu, Kyle Allen Emmitte, Yu-Chieh Wang

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background: Although NGLY1 is known as a pivotal enzyme that catalyses the deglycosylation of denatured glycoproteins, information regarding the responses of human cancer and normal cells to NGLY1 suppression is limited. Methods: We examined how NGLY1 expression affects viability, tumour growth, and responses to therapeutic agents in melanoma cells and an animal model. Molecular mechanisms contributing to NGLY1 suppression-induced anticancer responses were revealed by systems biology and chemical biology studies. Using computational and medicinal chemistry-assisted approaches, we established novel NGLY1-inhibitory small molecules. Results: Compared with normal cells, NGLY1 was upregulated in melanoma cell lines and patient tumours. NGLY1 knockdown caused melanoma cell death and tumour growth retardation. Targeting NGLY1 induced pleiotropic responses, predominantly stress signalling-associated apoptosis and cytokine surges, which synergise with the anti-melanoma activity of chemotherapy and targeted therapy agents. Pharmacological and molecular biology tools that inactivate NGLY1 elicited highly similar responses in melanoma cells. Unlike normal cells, melanoma cells presented distinct responses and high vulnerability to NGLY1 suppression. Conclusion: Our work demonstrated the significance of NGLY1 in melanoma cells, provided mechanistic insights into how NGLY1 inactivation leads to eradication of melanoma with limited impact on normal cells, and suggested that targeting NGLY1 represents a novel anti-melanoma strategy.

Original languageEnglish
Pages (from-to)1538-1551
Number of pages14
JournalBritish Journal of Cancer
Volume119
Issue number12
DOIs
StatePublished - 11 Dec 2018

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Interferons
Melanoma
Apoptosis
Neoplasms
Systems Biology
Pharmaceutical Chemistry
Growth
Tumor Cell Line
Molecular Biology
Glycoproteins
Cell Death
Animal Models
Pharmacology
Cytokines
Drug Therapy
Enzymes
Therapeutics

Cite this

Zolekar, Ashwini ; Lin, Victor J.T. ; Mishra, Nigam M. ; Ho, Yin Ying ; Hayatshahi, Hamed S. ; Parab, Abhishek ; Sampat, Rohit ; Liao, Xiaoyan ; Hoffmann, Peter ; Liu, Jin ; Emmitte, Kyle Allen ; Wang, Yu-Chieh. / Stress and interferon signalling-mediated apoptosis contributes to pleiotropic anticancer responses induced by targeting NGLY1. In: British Journal of Cancer. 2018 ; Vol. 119, No. 12. pp. 1538-1551.
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abstract = "Background: Although NGLY1 is known as a pivotal enzyme that catalyses the deglycosylation of denatured glycoproteins, information regarding the responses of human cancer and normal cells to NGLY1 suppression is limited. Methods: We examined how NGLY1 expression affects viability, tumour growth, and responses to therapeutic agents in melanoma cells and an animal model. Molecular mechanisms contributing to NGLY1 suppression-induced anticancer responses were revealed by systems biology and chemical biology studies. Using computational and medicinal chemistry-assisted approaches, we established novel NGLY1-inhibitory small molecules. Results: Compared with normal cells, NGLY1 was upregulated in melanoma cell lines and patient tumours. NGLY1 knockdown caused melanoma cell death and tumour growth retardation. Targeting NGLY1 induced pleiotropic responses, predominantly stress signalling-associated apoptosis and cytokine surges, which synergise with the anti-melanoma activity of chemotherapy and targeted therapy agents. Pharmacological and molecular biology tools that inactivate NGLY1 elicited highly similar responses in melanoma cells. Unlike normal cells, melanoma cells presented distinct responses and high vulnerability to NGLY1 suppression. Conclusion: Our work demonstrated the significance of NGLY1 in melanoma cells, provided mechanistic insights into how NGLY1 inactivation leads to eradication of melanoma with limited impact on normal cells, and suggested that targeting NGLY1 represents a novel anti-melanoma strategy.",
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Stress and interferon signalling-mediated apoptosis contributes to pleiotropic anticancer responses induced by targeting NGLY1. / Zolekar, Ashwini; Lin, Victor J.T.; Mishra, Nigam M.; Ho, Yin Ying; Hayatshahi, Hamed S.; Parab, Abhishek; Sampat, Rohit; Liao, Xiaoyan; Hoffmann, Peter; Liu, Jin; Emmitte, Kyle Allen; Wang, Yu-Chieh.

In: British Journal of Cancer, Vol. 119, No. 12, 11.12.2018, p. 1538-1551.

Research output: Contribution to journalArticle

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AU - Zolekar, Ashwini

AU - Lin, Victor J.T.

AU - Mishra, Nigam M.

AU - Ho, Yin Ying

AU - Hayatshahi, Hamed S.

AU - Parab, Abhishek

AU - Sampat, Rohit

AU - Liao, Xiaoyan

AU - Hoffmann, Peter

AU - Liu, Jin

AU - Emmitte, Kyle Allen

AU - Wang, Yu-Chieh

PY - 2018/12/11

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N2 - Background: Although NGLY1 is known as a pivotal enzyme that catalyses the deglycosylation of denatured glycoproteins, information regarding the responses of human cancer and normal cells to NGLY1 suppression is limited. Methods: We examined how NGLY1 expression affects viability, tumour growth, and responses to therapeutic agents in melanoma cells and an animal model. Molecular mechanisms contributing to NGLY1 suppression-induced anticancer responses were revealed by systems biology and chemical biology studies. Using computational and medicinal chemistry-assisted approaches, we established novel NGLY1-inhibitory small molecules. Results: Compared with normal cells, NGLY1 was upregulated in melanoma cell lines and patient tumours. NGLY1 knockdown caused melanoma cell death and tumour growth retardation. Targeting NGLY1 induced pleiotropic responses, predominantly stress signalling-associated apoptosis and cytokine surges, which synergise with the anti-melanoma activity of chemotherapy and targeted therapy agents. Pharmacological and molecular biology tools that inactivate NGLY1 elicited highly similar responses in melanoma cells. Unlike normal cells, melanoma cells presented distinct responses and high vulnerability to NGLY1 suppression. Conclusion: Our work demonstrated the significance of NGLY1 in melanoma cells, provided mechanistic insights into how NGLY1 inactivation leads to eradication of melanoma with limited impact on normal cells, and suggested that targeting NGLY1 represents a novel anti-melanoma strategy.

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