Biology of Colon Cancer Resistance to Treatment

Abstract In cancer, resistance to chemotherapy is one of the main reasons for therapeutic failure. Cells that survive after treatment with anticancer drugs undergo various changes, including in cell metabolism. In this study, we investigated the effects of AKT-mediated miR-125b-5p alteration on metabolic changes and examined how these molecules enhance migration and induce drug resistance in colon cancer cells. AKT1 and AKT3 activation in drug-resistant colon cancer cells caused aberrant downregulation of miR-125b-5p, leading to GLUT5 expression. Targeted inhibition of AKT1 and AKT3 restored miR-125b-5p expression and prevented glycolysis- and lipogenesis-related enzyme activation. In addition, restoring the level of miR-125b-5p by transfection with the mimic sequence not only significantly blocked the production of lactate and intracellular fatty acids but also suppressed the migration and invasion of chemoresistant colon cancer cells. GLUT5 silencing with small interfering RNA attenuated mesenchymal marker expression and migratory activity in drug-resistant colon cancer cells. Additionally, treatment with 2,5-anhydro-d-mannitol resensitized chemoresistant cancer cells to oxaliplatin and 5-fluorouracil. In conclusion, our findings suggest that changes in miR-125b-5p and GLUT5 expression after chemotherapy can serve as a new marker to indicate metabolic change-induced migration and drug resistance development.

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Prooxidative Activity of Celastrol Induces Apoptosis, DNA Damage, and Cell Cycle Arrest in Drug-Resistant Human Colon Cancer Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/6793957 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 6

Author(s):

Helena Moreira ◽

Anna Szyjka ◽

Kamila Paliszkiewicz ◽

Ewa Barg

Keyword(s):

Cell Cycle ◽

Colon Cancer ◽

Cell Death ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Phase Cell ◽

Drug Resistant ◽

Cancer Resistance ◽

Colon Cancer Cells ◽

Cycle Arrest

Cancer resistance to chemotherapy is closely related to tumor heterogeneity, i.e., the existence of distinct subpopulations of cancer cells in a tumor mass. An important role is assigned to cancer stem cells (CSCs), a small subset of cancer cells with high tumorigenic potential and capacity of self-renewal and differentiation. These properties of CSCs are sustained by the ability of those cells to maintain a low intracellular reactive oxygen species (ROS) levels, via upregulation of ROS scavenging systems. However, the accumulation of ROS over a critical threshold disturbs CSCs—redox homeostasis causing severe cytotoxic consequences. In the present study, we investigated the capacity of celastrol, a natural pentacyclic triterpenoid, to induce the formation of ROS and, consequently, cell death of the colon cancer cells with acquired resistant to cytotoxic drugs (LOVO/DX cell line). LOVO/DX cells express several important stem-like cell features, including a higher frequency of side population (SP) cells, higher expression of multidrug resistant proteins, overexpression of CSC-specific cell surface marker (CD44), increased expression of DNA repair gene (PARP1), and low intracellular ROS level. We found that celastrol, at higher concentrations (above 1 μM), significantly increased ROS amount in LOVO/DX cells at both cytoplasmic and mitochondrial levels. This prooxidant activity was associated with the induction of DNA double-strand breaks (DSBs) and apoptotic/necrotic cell death, as well as with inhibition of cell proliferation by S phase cell cycle arrest. Coincubation with NAC, a ROS scavenger, completely reversed the above effects. In summary, our results provide evidence that celastrol exhibits effective cytotoxic effects via ROS-dependent mechanisms on drug-resistant colon cancer cells. These findings strongly suggest the potential of celastrol to effectively kill cancer stem-like cells, and thus, it is a promising agent to treat severe, resistant to conventional therapy, colon cancers.

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Genomic Instability and TP53 Genomic Alterations Associate With Poor Antiproliferative Response and Intrinsic Resistance to Aromatase Inhibitor Treatment

JCO Precision Oncology ◽

10.1200/po.18.00286 ◽

2019 ◽

pp. 1-11

Author(s):

Eugene F. Schuster ◽

Pascal Gellert ◽

Corrinne V. Segal ◽

Elena López-Knowles ◽

Richard Buus ◽

...

Keyword(s):

Breast Cancer ◽

Aromatase Inhibitor ◽

Genomic Instability ◽

Loss Of Heterozygosity ◽

Cancer Resistance ◽

Wild Type ◽

Intrinsic Resistance ◽

Ki 67 ◽

Primary Tumors ◽

Resistance To Treatment

PURPOSE Although aromatase inhibitor (AI) treatment is effective in estrogen receptor–positive postmenopausal breast cancer, resistance is common and incompletely explained. Genomic instability, as measured by somatic copy number alterations (SCNAs), is important in breast cancer development and prognosis. SCNAs to specific genes may drive intrinsic resistance, or high genomic instability may drive tumor heterogeneity, which allows differential response across tumors and surviving cells to evolve resistance to treatment rapidly. We therefore evaluated the relationship between SCNAs and intrinsic resistance to treatment as measured by a poor antiproliferative response. PATIENTS AND METHODS SCNAs were determined by single nucleotide polymorphism array in baseline and surgery core-cuts from 73 postmenopausal patients randomly assigned to receive 2 weeks of preoperative AI or no AI in the Perioperative Endocrine Therapy—Individualizing Care (POETIC) trial. Fifty-six samples from the AI group included 28 poor responders (PrRs, less than 60% reduction in protein encoded by the MKI67 gene [Ki-67]) and 28 good responders (GdRs, greater than 75% reduction in Ki-67). Exome sequencing was available for 72 pairs of samples. RESULTS Genomic instability correlated with Ki-67 expression at both baseline ( P < .001) and surgery ( P < .001) and was higher in PrRs ( P = .048). The SCNA with the largest difference between GdRs and PrRs was loss of heterozygosity observed at 17p (false discovery rate, 0.08), which includes TP53. Nine of 28 PrRs had loss of wild-type TP53 as a result of mutations and loss of heterozygosity compared with three of 28 GdRs. In PrRs, somatic alterations of TP53 were associated with higher genomic instability, higher baseline Ki-67, and greater resistance to AI treatment compared with wild-type TP53. CONCLUSION We observed that primary tumors with high genomic instability have an intrinsic resistance to AI treatment and do not require additional evolution to develop resistance to estrogen deprivation therapy.

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Cancer resistance to treatment and antiresistance tools offered by multimodal multifunctional nanoparticles

Cancer Nanotechnology ◽

10.1186/s12645-017-0030-4 ◽

2017 ◽

Vol 8 (1) ◽

Cited By ~ 23

Author(s):

Eudald Casals ◽

Muriel F. Gusta ◽

Macarena Cobaleda-Siles ◽

Ana Garcia-Sanz ◽

Victor F. Puntes

Keyword(s):

Cancer Resistance ◽

Multifunctional Nanoparticles ◽

Resistance To Treatment

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Molecular Mechanisms Involved in the Acquisition of Resistance to Treatment of Colon Cancer Cells

Colorectal Cancer - From Pathogenesis to Treatment ◽

10.5772/63524 ◽

2016 ◽

Author(s):

Dora M. Velázquez ◽

María Cristina Castañeda-Patlán ◽

Martha Robles-Flores

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Colon Cancer Cells ◽

Resistance To Treatment

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Knockdown of PRDX2 sensitizes colon cancer cells to 5-FU by suppressing the PI3K/AKT signaling pathway

Bioscience Reports ◽

10.1042/bsr20160447 ◽

2017 ◽

Vol 37 (3) ◽

Cited By ~ 16

Author(s):

Jun Xu ◽

Shouru Zhang ◽

Rong Wang ◽

Xingye Wu ◽

Li Zeng ◽

...

Keyword(s):

Colon Cancer ◽

Protein Expression ◽

Cancer Cells ◽

Signaling Pathway ◽

Akt Signaling ◽

Cancer Resistance ◽

Colon Cancer Cells ◽

Akt Signaling Pathway ◽

Ros Scavenging ◽

Bax Protein

Although, 5-Fluorouracil (5-FU) remains widely used in adjuvant therapy in patients with colon cancer, resistance to 5-FU-based chemotherapy is an important reason for treatment failure. Recent studies have reported that an enhanced reactive oxygen species (ROS) scavenging system shows drug resistance to 5-FU. Peroxiredoxin-2 (PRDX2), is an important member of the ROS scavenging system, and may be a potential target that promotes chemosensitivity to 5-FU in colon cancer. Here, we depleted PRDX2 by PRDX2-shRNA-LV transduction in two colon cancer cell lines and found that in vitro PRDX2 knockdown facilitates cell death, and apoptosis in 5-FU-treated colon cancer cells. In addition, we found that PRDX2 depletion in mice treated with 5-FU resulted in, inhibition of tumor growth, compared with mice treated with 5-FU alone. Our data also suggested that the PI3K/AKT signaling pathway links PRDX2 with 5-FU-induced apoptosis in colon cancer. Furthermore, when PRDX2 was overexpressed in colon cancer cells, we found increased p-AKT protein expression and reduced Bcl-2/Bax protein expression. PRDX2 and p-AKT protein expression were analyzed by immunohistochemistry technology in human colon carcinoma tissues. Pearson correlation coefficient is 0.873 and P<0.05. PRDX2 depletion led to reduced p-AKT expression and PI3K/AKT pathway inhibition promoted cell apoptosis in HT29 cell line. Taken together, our study suggests that decreasing the expression of PRDX2 could be a promising strategy for increasing the sensitivity of colon cancer cells to 5-FU.

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