Abstract
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.
Highlights
Lung cancer is the leading cause of cancer mortality worldwide [1, 2]
We measured the weight of tumor-bearing lungs as well as dissected tumors from mice of the two genotypes and demonstrated that Nitrilase 1 (Nit1)+/+:KrasG12D/+ mice have a heavier tumor load
Nit1 deficient mice have a trend to live longer (Log-rank test for trend, ▲ P
Summary
Lung cancer is the leading cause of cancer mortality worldwide [1, 2]. It generally presents with genomic instability and abnormalities that researchers have exploited as novel sources for targeted therapeutics [3, 4]. The success of these research efforts in utilizing targeted therapeutics has aided clinicians in the management of lung cancer patients [5,6,7]. Present in about 20-30% of NSCLCs, lead to the over activation of the mitogen-activated protein kinase (MAPK) pathway, which has diverse impacts on cellular proliferation [9]. Mutations in the Kras pathway have continually led cancer patients to decreased responses to chemotherapeutics and radiation therapy treatments [10]. The overall decreased response rates due to activating mutations in NSCLCs make it critically important to find new targets
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