Abstract
Small cell lung cancer (SCLC) is a tumor characterized by rapid onset and a high propensity for metastasis. Treatment options are limited, having remained largely unchanged over the past few decades, and are quickly overcome by drug resistance. These factors are major contributors to the poor prognosis and unusually high mortality, which underscore an urgent need to identify novel biomarkers and therapeutic targets in order to improve the detection and treatment of SCLC. Thus, the overarching goal of our group is to identify molecular changes specific to SCLC cells relative to precancerous precursor cells and determine their roles in tumor growth.
In a previously published report, the Park lab demonstrated that the development of SCLC driven by Mycl depends on enhanced ribosome biogenesis and protein translation, and is sensitive to inhibition of RNA Polymerase I. Here, we sought to identify genes downstream of Mycl that could promote protein translation and be targeted to inhibit the growth of SCLC. While few studies have explored the metabolism of amino acids to target this tumor, we found that comparative profiling of precancerous cells and cells transformed by Mycl revealed branched chain aminotransferase 1 (Bcat1) as one of the most up-regulated genes in the transformed cells. Based on this observation, and the fact that branched chain amino acids (BCAAs) can contribute to the synthesis of non-essential amino acids, which are utilized for protein translation, we hypothesized that the overexpression of BCAT1 promotes the growth of SCLC.
Thus, in chapter 2, we confirm that BCAT1 protein levels are elevated in mouse SCLC cells relative to precancerous cells, and that BCAT1 is also expressed in a subset of human SCLC cells. Importantly, we found that BCAT1 promotes the growth of SCLC cells and tumors. We also found that BCAT1 reduces the intracellular concentration of valine, as well as increases the intracellular concentrations of glutamate and aspartate; additionally, we found that BCAT1 increases the catabolism of leucine. These findings are consistent with the concept that BCAT1 enhances the catabolism of BCAAs. As leucine is sensed by the mechanistic target of rapamycin complex 1 (mTORC1), which has been reported to support the growth of tumors by promoting protein translation, we investigated the role of BCAT1 in the mTORC1 pathway and found that the inhibition of BCAT1 results in notable increases in the phosphorylation of RPS6K and MTOR in SCLC cells, which suggests that BCAT1 inhibits mTORC1 in SCLC. Interestingly, we present data that suggest that BCAT1 does not decrease protein translation, but actually increases it under certain conditions. Taken together, these novel findings suggest that the elevated expression of BCAT1 supports the growth of SCLC, potentially by promoting protein translation. How BCAT1 promotes protein translation and inhibits mTORC1 remains elusive, but given the proven safety profile of an existing inhibitor of BCAT1, our findings are significant in supporting the concept of targeting BCAT1 as a novel and particularly valuable therapeutic strategy for SCLC.
