Nitrilase 1 modulates lung tumor progression in vitro and in vivo
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Yong Antican Wang1, Yunguang Sun2,5, Justin M. Le Blanc1, Charalambos Solomides3, Tingting Zhan4, Bo Lu1
1Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
2Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
3Department of Pathology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
4Department of Pharmacology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
5Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
Bo Lu, e-mail: [email protected]
Keywords: NIT1, lung cancer, KRAS, NSCLC, tumor suppressor
Received: October 01, 2015 Accepted: January 23, 2016 Published: March 10, 2016
Uncovering novel growth modulators for non-small cell lung cancer (NSCLC) may lead to new therapies for these patients. Previous studies suggest Nit1 suppresses chemically induced carcinogenesis of the foregut in a mouse model. In this study we aimed to determine the role of Nit1 in a transgenic mouse lung cancer model driven by a G12D Kras mutation. Nit1 knockout mice (Nit1−/−) were crossed with KrasG12D/+ mice to investigate whether a G12D Kras mutation and Nit1 inactivation interact to promote or inhibit the development of NSCLC. We found that lung tumorigenesis was suppressed in the Nit1-null background (Nit1−/−:KrasG12D/+). Micro-CT scans and gross tumor measurements demonstrated a 5-fold reduction in total tumor volumes compared to Nit1+/+KrasG12D/+ (p<0.01). Furthermore, we found that Nit1 is highly expressed in human lung cancer tissues and cell lines and use of siRNA against Nit1 decreased overall cell survival of lung cancer cells in culture. In addition, cisplatin response was enhanced in human lung cancer cells when Nit1 was knocked down and Nit1−/−:KrasG12D/+ tumors showed increased sensitivity to cisplatin in vivo. Together, our data indicate that Nit1 may play a supportive role in the modulation of lung tumorigenesis and represent a novel target for NSCLCs treatment.
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