ROLE OF SORD IN SUGAR-MEDIATED CANCER METASTASIS

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the USA. An estimated 53,200 people will die from CRC in 2020. Another disturbing fact is that the rates of incidence and mortality from young adults have been increasing since the 1990s for unknown reasons. The mortality of CRC patients is mainly attributed to tumor metastasis, a complex, multistep process. This proposal aims to uncover the underlying mechanisms that control CRC metastasis and the key pathways and environmental factors that contribute to it. One possible factor is sugar-sweetened beverages (SSBs), the consumption of which has dramatically increased in the past four decades. SSBs are any liquids that are sweetened with refined sugars, such as sucrose and high-fructose corn syrup (HFCS), both of which consist of glucose and fructose in a ratio of approximately 1:1. More than half of the adults in the USA consume SSBs on a given day. Epidemiological studies have shown a positive correlation between SSBs consumption and the recurrence of and mortality from advanced-stage CRC. However, it is still unclear whether SSB consumption can directly affect metastasis on advanced-stage CRC and, therefore mortality, independently of obesity. This question is critical because certain CRC patients regularly consume SSBs. Moreover, oncologists and nutritionists in the US recommend that their CRC patients drink energy drinks and concentrated juices—which are, in fact, SSBs with high amounts of added sugar—because these SSBs also contain calories, protein, and/or micronutrients. Our preliminary data show that a medium containing both glucose and fructose (hereafter, the HFCS condition) increased the migration and invasion of CRC cell lines (hereafter, CRC motility), which was correlated with an increased level of sorbitol. The deletion of a NAD(H)-dependent sorbitol dehydrogenase (SORD) decreased CRC motility and sorbitol level in the HFCS condition. Our xenograft mice models also showed that HFCS treatment increased CRC metastasis (local invasion and liver metastasis), and SORD was necessary for the metastasis. Notably, the loss of SORD also inhibited CRC motility in the high-glucose condition, in which glucose converts to fructose via the polyol pathway. It is known that chronic consumption of SSBs causes a high concentration of glucose in the blood. Thus, we hypothesize that SORD plays a key role in accelerating CRC metastasis by interacting with sugars. We propose three aims: Aim 1: Determine how SORD accelerates CRC motility in the HFCS condition. Aim 2: Determine how SORD increases CRC motility in the high-glucose condition. Aim 3: Understand the role of SORD in CRC metastasis. Successful completion of these proposed studies will characterize SORD as a novel therapeutic target for CRC metastasis. Further, our results will identify metabolic pathways and metabolites that may serve as new biomarkers or targets for preventing CRC metastasis. Finally, our study will highlight the danger of HFCS consumption, especially in the form of SSBs, which may accelerate CRC metastasis. This will change current clinical practices and dietary guidelines for CRC patients, significantly reducing CRC mortality.