scholarly journals MiR-454-3p Promotes Oxaliplatin Resistance by Targeting PTEN in Colorectal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiao-Lan Qian ◽  
Fang Zhou ◽  
Song Xu ◽  
Jian Jiang ◽  
Zhi-Peng Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Acquired Resistance ◽  
Progression Free Survival ◽  
Underlying Mechanism ◽  
Oxaliplatin Treatment ◽  
Colorectal Cancer Cells ◽  
Cellular Apoptosis ◽  
Hct 116 ◽  
Resistant Cells

Colorectal cancer is one of the most common malignancies worldwide. Oxaliplatin is the first-line chemotherapeutic agent for the treatment of advanced colorectal cancer. However, acquired resistance to oxaliplatin limits its therapeutic efficacy, and the underlying mechanism remains largely unclear. In this study, we compared the expression of a panel of microRNAs (miRNAs) between oxaliplatin-sensitive and -resistant HCT-116 colorectal cancer cells. We found that miR-454-3p was significantly up-regulated in oxaliplatin-resistant cells and was the most differently expressed miRNA. Interestingly, we observed that inhibition of miR-454-3p resensitized resistant cells to oxaliplatin and enhanced oxaliplatin-induced cellular apoptosis. Moreover, we determined that miR-454-3p promoted oxaliplatin resistance through targeting PTEN and activating the AKT signaling pathway. In vivo study revealed that overexpression of miR-454-3p decreased the sensitivity of HCT-116 xenograft tumors to oxaliplatin treatment in a mouse model. Clinically, overexpression of miR-454-3p was associated with decreased responsiveness to oxaliplatin-based chemotherapy, as well as a short progression-free survival. Taken together, our study indicated that the expression of miR-454-3p could be used to predict oxaliplatin sensitivity, and targeting miR-454-3p could overcome oxaliplatin resistance in colorectal cancer.

Knockdown of aquaporin-5 sensitizes colorectal cancer cells to 5-fluorouracil via inhibition of the Wnt–β-catenin signaling pathway

2018 ◽  
Vol 96 (5) ◽  
pp. 572-579 ◽  
Author(s):  
Qing Li ◽  
Tao Yang ◽  
Dongsheng Li ◽  
Feng Ding ◽  
Guang Bai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Growth ◽  
Water Channel ◽  
Resistant Mutant ◽  
Underlying Mechanism ◽  
Aquaporin 5 ◽  
Protein Levels ◽  
Colorectal Cancer Cells ◽  
Underlying Mechanisms

Aquaporin-5 (AQP5), a water channel protein, has been reported to possess oncogenic potential in multiple types of malignancies, including colorectal cancer (CRC). However, its effect on the chemosensitivity of CRC cells remains elusive. Hence, this study investigated the effect of AQP5 silencing in CRC cells on 5-fluorouracil (5-FU) sensitivity and attempted to elucidate the underlying mechanisms. A short hairpin RNA construct targeting AQP5 was transfected into HCT116 or HT29 cells to generate stable AQP5-silenced cell lines. The effects of AQP5 knockdown on cell viability, apoptosis, tumor growth, and 5-FU chemoresistance were evaluated. Relative protein levels of Wnt–β-catenin pathway effectors were also measured. The results showed that silencing of AQP5 increased the chemosensitivity of CRC cells to 5-FU, facilitated 5-FU-mediated apoptosis, suppressed tumor growth, and reduced 5-FU chemoresistance in vivo. Furthermore, the effect of AQP5 on 5-FU chemosensitivity was mediated by the Wnt–β-catenin pathway. Silencing of AQP5 inhibited Wnt–β-catenin signaling, whereas overexpression of the degradation-resistant mutant of β-catenin (S33Y) reversed apoptosis induced by AQP5 silencing. Taken together, these results suggest that AQP5 silencing enhances the sensitivity of CRC cells to 5-FU, and the underlying mechanism is related to inhibition of the Wnt–β-catenin pathway. AQP5 could be a useful therapeutic target for CRC treatment.

Role of sphingosine kinase 1 (SphK1) on cetuximab resistance in colorectal cancer models.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13509-e13509
Author(s):  
Roberto Bianco ◽  
Roberta Rosa ◽  
Lucia Nappi ◽  
Luigi Formisano ◽  
Vincenzo Damiano ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Anticancer Agents ◽  
Acquired Resistance ◽  
Sphingosine Kinase ◽  
Sphingosine Kinase 1 ◽  
Mutational Status ◽  
Resistant Cells

e13509 Background: Although EGFR inhibitors, such as the mAb cetuximab, represent an effective strategy in colorectal cancer (CRC), the clinical use of these agents is limited by intrinsic or acquired resistance. Alterations in the ‘sphingolipid rheostat’, or the balance between the proapoptotic molecule ceramide and the mitogenic factor sphingosine-1-phosphate (S1P), due to overactivation of sphingosine kinase 1 (SphK1), have been involved in the regulation of resistance to anticancer agents. Since some studies described cross-talks between SphK1 and EGFR-dependent signalling pathways, we investigated the contribution of SphK1 to cetuximab resistance in CRC models. Methods: We used CRC cell lines with both intrinsic or acquired resistance to cetuximab. In these models, we analyzed SphK1 expression/activation by using different tools, including the available drug fingolimod (FTY720), both in vitro and in vivo. We confirmed our data through a tissue microarray (TMA)-based analysis on CRC tissues. Results: SphK1 is overexpressed in CRC cells resistant to cetuximab. Higher doses of N,N-dimethylsphingosine (DMS), a potent competitive inhibitor of SphK1, are needed to achieve complete enzyme saturation and survival inhibition in resistant cells. Moreover, ceramide induces apoptosis less efficiently in resistant than in sensitive cells, consistently with the idea that increased SphK1 levels mediate S1P synthesis by ceramide in resistant cells. SphK1 contribution to resistance is supported by the demonstration that SphK1 inhibition by DMS or silencing via siRNA in resistant cells restores sensitivity to cetuximab, whereas exogenous SphK1 overexpression in wild-type cells confers resistance. Re-sensitization to cetuximab is observed after treatment with fingolimod, a S1P receptor inhibitor, both in vitro and in nude mice xenografted with CRC cells. Finally, a TMA-based analysis on CRC tissues revealed that SphK1 expression is related to K-Ras mutational status, a well-known determinant of cetuximab resistance. Conclusions: Our data could clarify the role of SphK1 in the onset of resistance to cetuximab, thus suggesting SphK1 inhibition as a part of novel targeting strategies for resistant cancer patients.

scholarly journals Cryptotanshinone Inhibits the Growth of HCT116 Colorectal Cancer Cells Through Endoplasmic Reticulum Stress-Mediated Autophagy

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaojing Fu ◽  
Wenwen Zhao ◽  
Kangkang Li ◽  
Jingyi Zhou ◽  
Xuehong Chen
Keyword(s):  
Colorectal Cancer ◽  
Er Stress ◽  
Salvia Miltiorrhiza ◽  
Underlying Mechanism ◽  
Drug Candidate ◽  
Drug Candidates ◽  
Colorectal Cancer Cells ◽  
Sw620 Cells

Among cancers, colorectal cancer (CRC) has one of the highest annual incidence and death rates. Considering severe adverse reactions associated with classical chemotherapy medications, traditional Chinese medicines have become potential drug candidates. In the current study, the effects of cryptotanshinone (CPT), a major component of Salvia miltiorrhiza Bunge (Danshen) on CRC and underlying mechanism were explored. First of all, data from in vitro experiments and in vivo zebrafish models indicated that CPT selectively inhibited the growth and proliferation of HCT116 and SW620 cells while had little effect on SW480 cells. Secondly, both ER stress and autophagy were associated with CRC viability regulation. Interestingly, ER stress inhibitor and autophagy inhibitor merely alleviated cytotoxic effects on HCT116 cells in response to CPT stimulation, while have little effect on SW620 cells. The significance of apoptosis, autophagy and ER stress were verified by clinical data from CRC patients. In summary, the current study has revealed the anti-cancer effects of CPT in CRC by activating autophagy signaling mediated by ER stress. CPT is a promising drug candidate for CRC treatment.

The Antitumor Activity of Betulinic Acid-Loaded Nanoliposomes Against Colorectal Cancer In Vitro and In Vivo via Glycolytic and Glutaminolytic Pathways

2020 ◽  
Vol 16 (2) ◽  
pp. 235-251
Author(s):  
Gang Wang ◽  
Yu-Zhu Wang ◽  
Yang Yu ◽  
Pei-Hao Yin ◽  
Ke Xu
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Cellular Uptake ◽  
Betulinic Acid ◽  
Anticancer Efficacy ◽  
Anti Cancer ◽  
Colorectal Cancer Cells ◽  
Cellular Apoptosis

The purpose of this study is to develop betulinic acid loaded nanoliposomes to improve the chemotherapy effect of colorectal cancer. The cellular uptake and anti-tumor effects of betulinic acid loaded nanoliposomes in vitro were characterized and evaluated, and their effects on glycolysis, glutamine decomposition and key anti-cancer targets were analyzed. Moreover, their anticancer efficacy was assessed in vivo. Compared with free betulinic acid in vitro, the cellular uptake and anti-tumor activity of betulinic acid-loaded nanoliposomes were significantly enhanced; these nanoliposomes significantly suppressed the proliferation and glucose uptake of colorectal cancer cells. Mechanistically, the anti-colorectal cancer effect of betulinic acid-loaded nanoliposomes was confirmed by their triggering of cellular apoptosis and regulating the potential glycolytic and glutaminolytic targets and pathways. After tumor proliferation was inhibited and colorectal cancer cells apoptosis, the anticancer effect of betulinic acid loaded nanoliposomes in vivo was significantly enhanced. All in all, betulinic acid loaded nanoliposomes are expected to be an effective drug delivery system for colorectal cancer treatment.

scholarly journals Effects of radiofrequency radiation on colorectal cancer cell proliferation and inflammation

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Elcin Ozgur ◽  
Handan Kayhan ◽  
Gorkem Kismali ◽  
Fatih Senturk ◽  
Merve Sensoz ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cell ◽  
Colorectal Cancer Cell ◽  
Radiofrequency Radiation ◽  
Protein Levels ◽  
Intermittent Exposure ◽  
Colorectal Cancer Cells ◽  
Colorectal Cancer Cell Lines ◽  
Hct 116 ◽  
Hct 116 Cells

Abstract Objectives The aim of this study is to investigate the effects of radiofrequency radiation (RFR) on apoptosis, proliferation, stress response, and inflammation markers in colorectal cancer cells. Methods We tested the effects of intermittent exposure to RFR at different frequencies on two different colorectal cancer cell lines; HCT-116 and DLD-1. Protein levels were subsequently analyzed by ELISA. Results RFR led to a decrease in P53, p-P53, p-P38, and p-IkB levels in HCT-116 cells, while leading to an increase in BAD, p-BAD, p-STAT3,NF-κB levels. Two thousand one hundred Megahertz of RFR altered the P53, BAD, and NF-ΚB expression in HCT-116 cells. P53, p-P53, BAD, p-BAD, NF-κB, p-NF-κB, p-P38, p-SAPK/JNK, p-STAT3, and p-IkB levels increased after exposure to RFR at 900 and 2,100 MHz in DLD-1 cells. Unlike HCT-116 cells, 1,800 MHz of RFR was reported to have no effect on DLD1 cells. Conclusions RFR increased apoptosis and inflammatory response in HCT116 cells, while lowering the active P38 and active P53 levels, which are indicators of poor prognosis in several cancers. Genetic differences, such as P53 mutation (DLD-1), are critical to the cell response to RFR, which explains the reason why scientific studies on the effects of RFR yield contradictory results.

scholarly journals Dehydrodiisoeugenol inhibits colorectal cancer growth by endoplasmic reticulum stress-induced autophagic pathways

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Changhong Li ◽  
Kui Zhang ◽  
Guangzhao Pan ◽  
Haoyan Ji ◽  
Chongyang Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Endoplasmic Reticulum ◽  
Cell Growth ◽  
Er Stress ◽  
Cancer Cells ◽  
Tumor Xenograft ◽  
Anticancer Activities ◽  
Colorectal Cancer Cells

Abstract Background Dehydrodiisoeugenol (DEH), a novel lignan component extracted from nutmeg, which is the seed of Myristica fragrans Houtt, displays noticeable anti-inflammatory and anti-allergic effects in digestive system diseases. However, the mechanism of its anticancer activity in gastrointestinal cancer remains to be investigated. Methods In this study, the anticancer effect of DEH on human colorectal cancer and its underlying mechanism were evaluated. Assays including MTT, EdU, Plate clone formation, Soft agar, Flow cytometry, Electron microscopy, Immunofluorescence and Western blotting were used in vitro. The CDX and PDX tumor xenograft models were used in vivo. Results Our findings indicated that treatment with DEH arrested the cell cycle of colorectal cancer cells at the G1/S phase, leading to significant inhibition in cell growth. Moreover, DEH induced strong cellular autophagy, which could be inhibited through autophagic inhibitors, with a rction in the DEH-induced inhibition of cell growth in colorectal cancer cells. Further analysis indicated that DEH also induced endoplasmic reticulum (ER) stress and subsequently stimulated autophagy through the activation of PERK/eIF2α and IRE1α/XBP-1 s/CHOP pathways. Knockdown of PERK or IRE1α significantly decreased DEH-induced autophagy and retrieved cell viability in cells treated with DEH. Furthermore, DEH also exhibited significant anticancer activities in the CDX- and PDX-models. Conclusions Collectively, our studies strongly suggest that DEH might be a potential anticancer agent against colorectal cancer by activating ER stress-induced inhibition of autophagy.

scholarly journals Extract of Pogostemon cablin Possesses Potent Anticancer Activity against Colorectal Cancer Cells In Vitro and In Vivo

2020 ◽  
Vol 2020 ◽  
pp. 1-11 ◽  
Author(s):  
Ju-Huei Chien ◽  
Shan-Chih Lee ◽  
Kai-Fu Chang ◽  
Xiao-Fan Huang ◽  
Yi-Ting Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Apoptosis ◽  
Cycle Arrest ◽  
Anticancer Effects ◽  
Pogostemon Cablin ◽  
Colorectal Cancer Cells ◽  
Potential Applicability ◽  
Cancer Suppression

Pogostemon cablin (PCa), an herb used in traditional Chinese medicine, is routinely used in the amelioration of different types of gastrointestinal discomfort. However, the mechanisms underlying the cancer suppression activity of PCa in colorectal cancer (CRC) cells have yet to be clarified. The aim of this study was to investigate the anticancer effects of PCa, specifically the induction of apoptosis in CRC cells. The growth inhibition curve of CRC cells following exposure to PCa was detected by an MTT assay. Moreover, PCa combined with 5-FU revealed a synergic effect of decreased cell viability. PCa inhibited cell proliferation and induced cell cycle arrest at the G0/G1 phase and cell apoptosis through regulation of associated protein expression. An in vivo study showed that PCa suppressed the growth of CRC via induction of cell apoptosis with no significant change in body weight or organ histology. Our results demonstrated that PCa inhibits the growth of CRC cells and induces apoptosis in vitro and in vivo, which suggests the potential applicability of PCa as an anticancer agent.

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