TY - JOUR
T1 - Stress and interferon signalling-mediated apoptosis contributes to pleiotropic anticancer responses induced by targeting NGLY1
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 A.
AU - Wang, Yu Chieh
N1 - Funding Information:
Funding: This work is supported by the UNTHSC Start-up Fund for Stem Cell Laboratory and Faculty Pilot Grant FY15 (RI6182) to Y.C.W, Start-up Fund for Medicinal Chemistry Laboratory to K.A.E., and Start-up Fund for Computational Chemistry Laboratory to J.L. V.J.T.L. is supported by the NIH NRSA Institutional Predoctoral Training Grant (T32 AG020494), and predoctoral fellowships from the American Medical Association (AMA) Foundation and the Cancer Prevention Research Institute of Texas (CPRIT; RP170301). Y.Y.H. and P.H. are supported by the Ovarian Cancer Research Foundation.
Publisher Copyright:
© 2018, The Authors.
PY - 2018/12/11
Y1 - 2018/12/11
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85055978337&partnerID=8YFLogxK
U2 - 10.1038/s41416-018-0265-9
DO - 10.1038/s41416-018-0265-9
M3 - Article
C2 - 30385822
AN - SCOPUS:85055978337
SN - 0007-0920
VL - 119
SP - 1538
EP - 1551
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 12
ER -