The mechanism and therapeutic potential of Parkin in colorectal cancer

About This Grant

Summary/Abstract: Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer death in the United States. A better understanding of the mechanisms of CRC will provide novel molecular targets and strategies for CRC therapies. Recent studies suggest that the E3 ubiquitin ligase Parkin plays a crucial role in the suppression of CRC. Parkin expression is frequently downregulated in CRC, and its downregulation is associated with poor prognosis of cancer patients. Currently, the precise role and mechanisms of Parkin in CRC are not well understood, hindering the development of effective therapeutic strategies for CRC. Metabolic reprogramming is a key contributor to cancer progression. Targeting specific metabolic alterations in cancer has become an emerging therapy for cancer. To delineate the novel and critical tumor-suppressive mechanisms of Parkin in CRC and provide novel molecular targets and therapeutic strategies for Parkin-deficient CRC, we employed unbiased screening approaches in our preliminary studies, including LC-MS/MS-based protein-protein interaction analysis and quantitative proteomic analysis. Our preliminary results show that Parkin regulates metabolism through ubiquitination and degradation of key metabolic enzymes in different metabolic pathways in CRC, and furthermore, Parkin deficiency results in the upregulation of these metabolic enzymes and metabolic reprogramming to promote CRC. Notably, targeting these metabolic enzymes and related pathways by specific small molecule inhibitors preferentially suppresses the progression of Parkin-deficient CRC. Based on these preliminary results, we hypothesize that Parkin plays a critical role in the suppression of CRC through ubiquitination of key metabolic enzymes, and Parkin deficiency in CRC leads to the upregulation of these metabolic enzymes and metabolic reprogramming to promote CRC, which can be targeted for therapy. In this proposed study, we will delineate the anti-cancer role and mechanisms of Parkin in CRC and evaluate the novel molecular targets and strategies to treat Parkindeficient CRC. To test our hypothesis, different human CRC cell lines, small molecule inhibitors, orthotopic tumor models, genetically engineered mouse models, and patient-derived CRC organoids will be employed. Mouse models will be used since they are excellent and appropriate in vivo models to study the role and mechanisms of Parkin in CRC and its potential therapeutic application, which cannot be replaced by cultured cells or other in vitro assays in our proposed studies. We anticipate that this study will: 1) delineate the critical anti-cancer role and mechanisms of Parkin in CRC; 2) provide novel mechanisms of metabolic reprogramming in CRC; and 3) provide a strong rationale and proof of concept for developing novel molecular targets and strategies to treat CRC, especially Parkin-deficient CRC, which is urgently needed in the clinic.