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Background/aim Cancer stem cell characteristics and drug resistance of colorectal cancer are associated with failure of cancer treatment. In this study, we investigated the effects of PrPC on cancer stem cell characteristics, migration, invasion, and drug resistance of 5FU-resistant CRC cells. Materials and methods PrPC negative and PrPC positive cells were isolated from 5FU-resistant CRC cells using magnetic activated cell sorting. Sphere formation, cancer stem cell marker expression, migration, invasion, and drug resistance were analyzed. Results PrPC positive cells showed increased sphere formation capacity and increased expression of cancer stem cell markers compared to PrPC negative cells. In addition, PrPC positive cells showed increased migration, invasion and drug resistance compared to PrPC negative cells. Furthermore, knockdown of PrPC abolished these effects. Conclusion PrPC expression is important in CRC cell behavior, such as sphere formation, migration, invasion, and drug resistance. PrPC is an important therapeutic target for the treatment of CRC.

Background/aim Administration of cisplatin in cancer patients is limited by the kidney-related adverse effects; however, a protective strategy is absent. We hypothesized that fucoidan protects the proximal tubule epithelial (TH-1) cells against the effects of cisplatin. Materials and methods To assess the effect of fucoidan, its effect on reactive oxygen species (ROS) formation, endoplasmic reticulum (ER) stress response, DNA damage response (DDR), apoptosis, and cell-cycle arrest in TH-1 cells was investigated. Results Cisplatin increased the accumulation of ROS, leading to excessive ER stress. In presence of cisplatin, treatment of TH-1 cells with fucoidan significantly reduced the ER stress by maintaining the complex of GRP78 with PERK and IRE1α. In particular, fucoidan enhanced the antioxidative capacity through up-regulation of PrPC Furthermore, fucoidan suppressed cisplatin-induced apoptosis and cell-cycle arrest, whereas silencing of PRNP blocked these effects of fucoidan. Conclusion Fucoidan may be a potential adjuvant therapy for cancer patients treated with cisplatin as it preserves renal functionality.

Cancer stem cell characteristics and drug resistance of colorectal cancer are associated with failure of cancer treatment. In this study, we investigated the effects of PrPPrPPrPPrP

Background Elevated production of reactive oxygen species (ROS) is observed in various cancer types and pathophysiological conditions. In cancer cells, ROS induce cell proliferation, genetic instability, and a malignant phenotype. Ginsenoside Rg3 is the main pharmacologically active component in ginseng and has been reported to have an antioxidant effect. To overcome lung cancer by regulating the ROS level, we investigated the antitumor effect and mechanism of Rg3 and its antioxidative property on Lewis lung carcinoma (LLC) cells. Materials and methods Inhibition of ROS was suppressed in LLC cells by Rg3 treatment, and these cells were used to investigate the antioxidant, antiproliferative, and antitumor effects in LLC cells. Results ROS production was increased in cells grown in serum-containing media (conditioned media) compared to those grown in serum-free media. The high level of ROS induced LLC cell proliferation, but treatment with Rg3 (200 ng/ml) resulted in reduction of ROS, leading to inhibition of cell proliferation. Treatment with Rg3 significantly reduced cyclin and cyclin-dependent kinase expression in LLC cells. Additionally, Rg3 treatment significantly suppressed activation of mitogen-activated protein kinases and induced LLC cell apoptosis through activation of pro-apoptotic proteins and suppression of anti-apoptotic proteins. Conclusion Taken together, these findings demonstrate the role of Rg3 in reduction of the intracellular ROS level, attenuation of proliferation via augmentation of cell cycle- and cell proliferation-associated proteins, and activation of apoptosis through regulation of apoptosis-associated proteins in LLC. These findings suggest that Rg3 could be used as a therapeutic agent in lung cancer.

Background/aim Drug resistance restricts the efficacy of chemotherapy in colorectal cancer. However, the detailed molecular mechanism of drug resistance in colorectal cancer cells remains unclear. Materials and methods The level of cellular prion protein (PrPC) in oxaliplatin-resistant colorectal cancer (SNU-C5/Oxal-R) cells was assessed. Results PrPC level in SNU-C5/Oxal-R cells was significantly increased compared to that in wild-type (SNU-C5) cells. Superoxide dismutase and catalase activities were higher in SNU-C5/Oxal-R cells than in SNU-C5 cells. Treatment of SNU-C5/Oxal-R cells with oxaliplatin and melatonin reduced PrPC expression, while suppressing antioxidant enzyme activity and increasing superoxide anion generation. In SNU-C5/Oxal-R cells, endoplasmic reticulum stress and apoptosis were significantly increased following co-treatment with oxaliplatin and melatonin compared to treatment with oxaliplatin alone. Conclusion Co-treatment with oxaliplatin and melatonin increased endoplasmic reticulum stress in and apoptosis of SNU-C5/Oxal-R cells through inhibition of PrPC, suggesting that PrPC could be a key molecule in oxaliplatin resistance of colorectal cancer cells.

5-Fluorouracil (5-FU) is an effective anticancer drug. However, the development of drug resistance has limited its chemotherapeutic efficacy. To address this problem, we investigated the expression of glucose-regulated protein (GRP78, 78 kDa) in 5-FU-resistant colorectal cancer (CRC) cells (SNUC5/5FUR). GRP78 was highly expressed in the SNUC5/5FUR cells compared to wild-type SNUC5 cells. In the presence of 5-FU, GRP78 knockdown induced apoptosis via activation of caspase-3 and poly(ADP-ribose)-polymerase 1. GRP78 also inhibited the production of intracellular reactive oxygen species by regulating stress-associated signaling pathways. Furthermore, GRP78 enhanced cell survival and proliferation via activation of the phosphatidylinosito-3-kinase-AKT-mammalian target of rapamycin axis and cell cycle-associated proteins. These effects were blocked upon GRP78 knockdown, which indicates that GRP78 is involved in the development of 5-FU resistance in these CRC cells. Therefore, a combination of chemotherapy and GRP78-specific targeting may counteract 5-FU resistance in CRC cells.

Background: The putative functions of the cellular prion protein (PrPc) are believed to be associated with cell signaling, differentiation, survival, and cancer progression. With respect to cancer development and progression, elevations and mutations of PrPc expression have been shown to increase the risk for malignancy and metastasis in breast and colorectal cancer. Since both natural supplements and direct regulation of PrPc expression contribute to inhibition of cancer progression and growth, we hypothesized that knockdown of PrPc could lead to an enhanced synergic effect on the inhibition of cancer growth by fucoidan. Materials and Methods: PrPc expression was suppressed in HT29 human colon cancer cells by utilizing small-interfering RNA (si-PRNP), and cells were subsequently used to study the antiproliferative and anticancer effects of fucoidan treatment of HT29 human colon cancer cells. Results: Fucoidan treatment significantly inhibited growth and reduced cyclin and cyclin-dependent kinase (CDK) expression in HT29 colon cancer cells. Furthermore, silencing PrPc expression with si-PRNP amplified the fucoidan-induced changes in cell proliferation, apoptosis, and migration. Intraperitoneal injection of si-PRNP with fucoidan reduced proliferation and tumor volume in Balb/c nude mice. This enhanced antitumor efficacy was associated with decreased angiogenesis. Conclusion: Combination of fucoidan with silencing of PrPc has a synergic effect on the inhibition of HT29 colon cancer cell growth. Furthermore, we provide evidence for the therapeutic application of PrPc silencing with other anticancer drugs for cancer.