Abstract
Pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) are notoriously challenging for treatment. Hyperactive nuclear factor κB (NF-κB) is a common culprit in both cancers. Previously, we discovered that protein arginine methyltransferase 5 (PRMT5) methylated and activated NF-κB. Here, we show that PRMT5 is highly expressed in PDAC and CRC. Overexpression of PRMT5 promoted cancer progression, while shRNA knockdown showed an opposite effect. Using an innovative AlphaLISA high throughput screen, we discovered a lead compound, PR5-LL-CM01, which exhibited robust tumor inhibition effects in both cancers. An in silico structure prediction suggested that PR5-LL-CM01 inhibits PRMT5 by binding with its active pocket. Importantly, PR5-LL-CM01 showed higher anti-tumor efficacy than the commercial PRMT5 inhibitor, EPZ015666, in both PDAC and CRC. This study clearly highlights the significant potential of PRMT5 as a therapeutic target in PDAC and CRC, and establishes PR5-LL-CM01 as a promising basis for new drug development in the future.
Highlights
Gastrointestinal cancer refers to malignant conditions of the gastrointestinal tract (GI tract) and accessory organs of digestion
We showed that protein arginine methyltransferase 5 (PRMT5) expression was significantly higher in various stages of Pancreatic ductal adenocarcinoma (PDAC), and in the metastatic stage, as compared to the normal PDAC adjacent tissue (Figure 1A, right panel, and Supplementary Figure S1A)
IHC assay of colorectal cancer (CRC) Tissue microarray (TMA) indicated that PRMT5 had much higher expression in samples ranging from inflammation, polyp, to the metastatic stage of CRC as compared to adjacent normal tissue (Figure 1B, right panel, and Supplementary Figure S1B)
Summary
Gastrointestinal cancer refers to malignant conditions of the gastrointestinal tract (GI tract) and accessory organs of digestion. Pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) are two of the most challenging cancer types. PDAC has a very poor prognosis with a median survival between 6-8 months [1, 2] and ~8% of. According to the American Cancer Society, PDACs represent the majority of the pancreatic cancer cases. The available options for treatment are hardly adequate in improving the quality of life of PDAC patients. Current therapy mainly consists of surgery, if diagnosed in the early stages. In more advanced stages, combined local treatment of radiation therapy and drugs such as gemcitabine plus nab-paclitaxel or FOLFIRINOX (combination of 5-flurouracil, leucovorin, irinotecan and www.impactjournals.com/oncotarget oxaliplatin) are used [3]. In addition to having a number of side effects, these therapeutic strategies barely increase the life span of the patient and provide little chance for a cure
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