Scientists who were studying a rare genetic disorder (NGLY1 deficiency) at the University of North Texas Health Science Center (UNTHSC) report the discovery of a novel targeted treatment for combating melanoma, a skin cancer that kills about 9,000 people in the U.S. States each year. Their study (“Stress and interferon signalling-mediated apoptosis contributes to pleiotropic anticancer responses induced by targeting NGLY1”) appears in the British Journal of Cancer.
“Although NGLY1 is known as a pivotal enzyme that catalyzes the deglycosylation of denatured glycoproteins, information regarding the responses of human cancer and normal cells to NGLY1 suppression is limited. We examined how NGLY1 expression affects viability, tumor 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.
“Compared with normal cells, NGLY1 was upregulated in melanoma cell lines and patient tumors. NGLY1 knockdown caused melanoma cell death and tumor growth retardation. Targeting NGLY1 induced pleiotropic responses, predominantly stress signaling-associated apoptosis and cytokine surges, which synergize 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.
“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.”
The discovery came when UNT System College of Pharmacy scientists were studying a missing protein that plays a role in NGLY1 deficiency, a disorder so rare that only about 60 patients worldwide have been diagnosed since it was identified in 2012. While trying to understand this newly identified genetic disorder, the team discovered that melanoma cells are surprisingly vulnerable to the loss of NGLY1 activity, said Yu-Chieh Wang, Ph.D., senior author and assistant professor of pharmaceutical sciences.
“People born with NGLY1 deficiency are alive while presenting developmental delays,” Dr. Wang said. “But when we studied the developmental variations caused by NGLY1, we found that the NGLY1 protein could be a very attractive cancer target.”
The team began exploring how the protein acts in the body and discovered that when NGLY1 was inhibited, normal cells survived, but melanoma cells did not.
“When melanoma cells lose NGLY1, they, in fact, die very quickly,” Dr. Wang said.
The study suggests that it is possible to eliminate melanoma cells without harming healthy cells by targeting NGLY1. The research could apply to other cancers as well. The next step is to understand why normal cells and some individuals survive even when the protein is missing, while cancer cells cannot survive without it.
“A promising discovery like ours could one day provide another way to overcome the cancer burden in humans,” noted Dr. Wang. “We will continuously work toward that goal based on our research findings.”