Results from limited research have previously suggested that conserved gene Nit1 acts as a tumor suppressor gene; however, new research from a team at Sidney Kimmel Cancer Center (Thomas Jefferson University, PA, USA) suggests that Nit1 may actually promote cancer growth.
The Sidney Kimmel team report that compared with normal cells, Nit1 is significantly overexpressed in common lung cancer. Furthermore, they demonstrated that silencing of Nit1 suppresses the growth of lung tumors. The findings, published recently in Oncotarget, point towards Nit1 as a potential new target for drug research and development.
“Lung cancer in most patients is becoming increasingly resistant to the therapies that exist today, making lung cancer the leading cause of cancer death worldwide,” commented senior study author Bo Lu (Sidney Kimmel Medical College). “There is a critical need for new agents, and an inhibitor of Nit1 may represent a new drug strategy.”
The researchers aimed to determine the role of Nit1 in a transgenic mouse lung cancer model driven by a G12D Kras mutation. They crossed either Nit1-knockout mice (Nit1-/-) or mice with an active Nit1 gene with KrasG12D/+ mice in order to investigate whether the interaction of a G12D Kras mutation and Nit1 inactivation promoted or inhibited non-small-cell lung cancer development.
The results showed that the mice with an active Nit1 gene developed tumors that were five-times larger than those developed by mice lacking Nit1. In addition, they showed that Nit1 is highly expressed in human lung cancer cell lines and tissues, and that survival of these cancer cells was decreased when Nit1 was silenced.
The team also looked into the effect of Nit1 inhibition on cisplatin response. They found that human lung cancer cells showed an enhanced response to cisplatin when Nit1 was knocked down and that Nit1-/-:KrasG12D/+ tumors demonstrated increased cisplatin sensitivity in vivo.
“The cancer was significantly more sensitive to cisplatin when Nit1 was silenced,” stated Dr Lu. “This is a story of discoveries – a tale of a false assumption that has led to a possible new drug strategy.”
Sources: Wang YA, Sun Y, Le Blanc JM, Solomides, Zhan T, Lu B. Nitrilase 1 modulates lung tumor progression in vitro and in vivo. Oncotarget. doi: 10.18632/oncotarget.7820 (2016) [Epub ahead of print]; Thomas Jefferson University press release