Search

Expression of hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) is known to play an important role in cancer progression in various cancer cell lines. Although genipin, a constituent of Gardenia fruit, has shown to have anti-tumor activity, its role in suppression of HIF-1 protein and downstream genes has yet to be clarified. We examined the effect of genipin on intracellular level of HIF-1α and extracellular level of VEGF proteins using colon cancer cell line HCT116. We observed genipin suppressed accumulation of HIF-1α under hypoxia in various cancer cell lines including HCT116. We found out suppressed accumulation of HIF-1α occurred through modulation of protein degradation. Genipin was also observed to suppress expression of VEGF and invasion of colon cancer cells through blocking of the ERK signaling pathway. Taken together, our results provide a new insight into the potential role of genipin in suppressing cancer progression of colon cancer cells. Citation Format: Dae-Hee Lee, Sang-Choul Oh, Suk-young Lee, Hong Jun Kim. Genipin inhibits invasion and migration of colon cancer cells by suppression of HIF1α accumulation and VEGF expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2061.

Reactive oxygen species modulator 1 (Romo1) is a novel protein that has been reported to be crucial for cancer cell proliferation and invasion. However, its clinical implications in colorectal cancer (CRC) patients are not well-known. For the first time, we investigated the association between Romo1 and the clinical outcomes of CRC patients. We examined Romo1 expression in resected tumor tissues immunohistochemically and assessed it with histological scores. We conducted survival analyses for patients who had curative resection (n=190) in accordance with clinical parameters including level of Romo1 expression, and we examined the association between Romo1 expression and cell invasion using Matrigel invasion assay in CRC cell lines. We observed significantly longer mean disease-free survival (DFS) in the low Romo1 group compared with the high Romo1 group (161 vs 127.6 months, p=0.035), and the median overall survival (OS) of the low Romo1 group was significantly longer than that of the high Romo1 group (196.9 vs 171.3 months, p=0.036). Cell invasiveness decreased in the Romo1 knockdown CRC cells in contrast to the controlled cells. Romo1 overexpression in tumor tissue was associated with a high lymph node ratio (LNR) between the metastatic and examined lymph nodes (p=0.025). Romo1 overexpression in tumor tissue was significantly associated with survival in curatively resected CRC patients, suggesting Romo1 expression as a potential adverse prognostic marker. Increased Romo1 expression was found to be associated with high LNR. Cancer invasiveness appeared to be a key reason for the poor survival related to highly expressed Romo1. Citation Format: Min Jee Jo, Hong Jun Kim, Suk-Young Lee, Dae-Hee Lee, Sang Cheul Oh. Reactive oxygen species modulator 1 (Romo1) predicts unfavorable prognosis in colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2254. doi:10.1158/1538-7445.AM2017-2254

Recent studies proved that an inactivation of RUNX3 (runt-related transcription factor-3) expression is highly associated with lymph node metastasis and poor prognosis in various cancer types. However, the mechanism of RUNX3-mediated suppression of tumor metastasis remains unclear. Herein, we aimed to clarify the effect of RUNX3 on metastasis and angiogenesis in colorectal cancer (CRC). First, we found that the reduction of expression of RUNX3 in CRC tissues when compared with tumor adjacent normal colon tissues, as indicated by reduced RUNX3 staining, was significantly correlated with TNM stage. Second, we demonstrated that RUNX3 overexpression inhibited CRC cell migration and invasion resulting from the elevated upregulation of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9) expression. In contrast, the knockdown of RUNX3 reduced the inhibition of migration and invasion of CRC cells. Last, Vascular endothelial growth factor(VEGF) is an inducer of angiogenesis and lymphangiogenesis. We found that restoration of RUNX3 decreased vascular endothelial growth factor (VEGF) secretion and suppressed endothelial cell growth and tube formation in CRC cells. Taken together, our data demonstrated that RUNX3 may provide insights into the development of RUNX3 for CRC metastasis diagnostics and therapeutics. Citation Format: Bo Ram Kim, Jung Lim Kim, Yoo Jin Na, Seong Hye Park, Sun Il Lee, Sanghee Kang, Sung Yup Joung, Suk Young Lee, Hong-Jun Kim, Dae-Hee Lee, Byung-Wook Min, Sang Cheul Oh. RUNX3 inhibits metastasis and angiogenesis in colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1617.

Recent studies have reported that metformin is an anti-diabetic drug, and is the potential a promising anti-cancer agent. The purpose of this study is to evaluate whether metformin effectively sensitize human colorectal cancer (CRC) cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Metformin alone did not induce apoptosis, but significantly potentiated TRAIL-induced apoptosis in CRC cells. CRC cells treated with metformin and TRAIL activated the intrinsic and extrinsic pathways of caspase activation. To elucidate the underlying mechanism, we found that metformin significantly reduced the protein levels of Mcl-1 (Myeloid cell leukemia 1) in CRC cells, and overexpression of Mcl-1 attenuated the cell death by metformin alone, or in combination with TRAIL. Further experiments revealed that metformin did not affect the mRNA level, but proteasomal degradation and protein stability of Mcl-1. The metformin-induced degradation of Mcl-1 required the E3 ligase Mule, which is responsible for the polyubiquitination of Mcl-1. Taken together, our study is the first report indicating that metformin enhances TRAIL-induced apoptosis through the degradation of Mcl-1 by the proteasome machinery. Citation Format: Seong Hye Park, Dae-Hee Lee, Jung Lim Kim, Sun Il Lee, Bo Ram Kim, Yoo Jin Na, Suk Young Lee, Hong-Jun Kim, Sung Yup Joung, Sanghee Kang, Sang Cheul Oh. Metformin enhances TRAIL-induced apoptosis by Mcl-1 degradation via Mule in colorectal cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3497.

Activation of sonic hedgehog (Shh) signaling has been involved in progression of various cancers. Cyclopamine uses as effective treatment for cancers in which hedgehog signaling is overexpressed. In this study, we elucidated that cyclopamine sensitizes to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in gastric cancer cells. Single treatment with cyclopamine or TRAIL could not induce significant cytotoxicity in gastric cancer cells. However, combination treatment of TRAIL with cyclopamine effectively led to caspase dependent apoptosis. We found that cyclopamine increased ER (Endoplasmic Reticulum) stress level in gastric cancer cells, and using ER stress inhibitor attenuated the cell death by cyclopamine. As further underlying mechanism, induction of ER stress by cyclopamine caused upregulation of JNK (c-Jun N-terminal kinases) protein, and then accumulation of p53 protein. We conducted experiment using p53 wild-type and p53-mutated gastric cancer cells, and this of particular importance since p53 wild-type gastric cancer cells had more significant efficacy than p53-mutated cells by cyclopamine. Accumulation of p53 increased DR5 protein. Taken together, we showed that cyclopamine sensitizes to TRAIL-induced apoptosis in gastric cancer cells. Citation Format: Yoo Jin Na, Dae-Hee Lee, Jung Lim Kim, Bo Ram Kim, Seong Hye Park, Byung-Wook Min, Sun Il Lee, SangHee Kang, Sung Yup Joung, Suk Young Lee, Hong-Jun Kim, Sang Cheul Oh. Cyclopamine enhances TRAIL-induced apoptosis by induction of DR5 via ER stress in gastric cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3512.