Kim, JungJin

Abstract Prostate-Specific Antigen (PSA) is a well-known diagnosis maker for detecting prostate cancer (PCa) using a serum test. However, PSA testing remains controversial because it shows a high false-positive rate and lacks the sensitivity of PCa patients with low PSA levels, although patients have metastasis. Recently, we found an E3 ubiquitin ligase, WSB1, highly expressed in PCa patients with low PSA levels. Overexpressed WSB1 is found in various human cancers, such as pancreatic cancer, lung cancer, breast cancer, and PCa. Especially with PCa, WSB1 is highly expressed in metastatic PCa. Using RNA seq. database from PCa patients (65 primaries and 25 metastasis), we found that WSB1 is highly expressed in 90% (9/10) of patients among ten primary patients with normal PSA levels and 100% (6/6) of patients among six metastasis patients with normal PSA levels. WSB1 expression shows a significant correlation with aggressive PCa progression. Furthermore, WSB1 can secrete into cell culture media like PSA. Therefore, we suggest that WSB1 could be a highly efficient marker combined with PSA for PCa diagnosis as well as being developed as a screening test for the early detection of PCa in the high-risk group. Citation Format: SeungBaek Lee, JungJin Kim. The development of a highly efficient diagnostic marker combined with PSA of prostate cancer (PCa) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 462.

Extracellular matrix stiffness controls DNA damage response.

Abstract Elucidating mechanisms of chemoresistance is critical to improve cancer therapy, especially for the treatment of pancreatic ductal adenocarcinoma (PDAC). Genome-wide association studies have suggested the less studied gene HEAT repeat-containing protein 1 (HEATR1) as a possible determinant of cellular sensitivity to different chemotherapeutic drugs. In this study, we assessed this hypothesized link in PDAC, where HEATR1 expression is downregulated significantly. HEATR1 silencing in PDAC cells increased resistance to gemcitabine and other chemotherapeutics, where this effect was associated with increased AKT kinase phosphorylation at the Thr308 regulatory site. Mechanistically, HEATR1 enhanced cell responsiveness to gemcitabine by acting as a scaffold to facilitate interactions between AKT and the protein phosphatase PP2A, thereby promoting Thr308 dephosphorylation. Consistent with these findings, treatment with the AKT inhibitor triciribine sensitized HEATR1-depleted PDAC cells to gemcitabine, suggesting that this therapeutic combination may overcome gemcitabine resistance in patients with low HEATR1 expression. Clinically, we found that HEATR1 downregulation in PDAC patients was associated with increased AKT phosphorylation, poor response to tumor resection plus gemcitabine standard-of-care treatment, and shorter overall survival. Collectively, our findings establish HEATR1 as a novel regulator of AKT and a candidate predictive and prognostic indicator of drug responsiveness and outcome in PDAC patients. Cancer Res; 76(3); 572–81. ©2015 AACR.