ALDH1A3 upregulation and spontaneous metastasis formation is associated with acquired chemoresistance in colorectal cancer cells

Abstract

BackgroundEfficiency of colorectal carcinoma treatment by chemotherapy is diminished as the resistance develops over time in patients. The same holds true for 5-fluorouracil, the drug used in first line chemotherapy of colorectal carcinoma.MethodsChemoresistant derivative of HT-29 cells was prepared by long-term culturing in increasing concentration of 5-fluorouracil. Cells were characterized by viability assays, flow cytometry, gene expression arrays and kinetic imaging. Immunomagnetic separation was used for isolation of subpopulations positive for cancer stem cells-related surface markers. Aldehyde dehydrogenase expression was attenuated by siRNA. In vivo studies were performed on SCID/bg mice.ResultsThe prepared chemoresistant cell line labeled as HT-29/EGFP/FUR is assigned with different morphology, decreased proliferation rate and 135-fold increased IC50 value for 5-fluorouracil in comparison to parental counterparts HT-29/EGFP. The capability of chemoresistant cells to form tumor xenografts, when injected subcutaneously into SCID/bg mice, was strongly compromised, however, they formed distant metastases in mouse lungs spontaneously. Derived cells preserved their resistance in vitro and in vivo even without the 5-fluorouracil selection pressure. More importantly, they were resistant to cisplatin, oxaliplatin and cyclophosphamide exhibiting high cross-resistance along with alterations in expression of cancer-stem cell markers such as CD133, CD166, CD24, CD26, CXCR4, CD271 and CD274. We also detected increased aldehyde dehydrogenase (ALDH) activity associated with overexpression of specific ALDH isoform 1A3. Its inhibition by siRNA approach partially sensitized cells to various agents, thus linking for the first time the ALDH1A3 and chemoresistance in colorectal cancer.ConclusionOur study demonstrated that acquired chemoresistance goes along with metastatic and migratory phenotype and can be accompanied with increased activity of aldehyde dehydrogenase. We describe here the valuable model to study molecular link between resistance to chemotherapy and metastatic dissemination.

Napabucasin overcomes cisplatin resistance in ovarian germ cell tumor-derived cell line by inhibiting cancer stemness

“…Despite the fact, that cisplatin-resistant NOY-1 CisR cells were also significantly more resistant to the ALDH inhibitors and napabucasin (STAT3 inhibitor downregulating ALDH expression), these drugs efficiently decreased ALDH activity of resistant cells. Inhibition of the ALDH activity might be a promising therapeutic approach to target the CSCs and to increase the effectiveness of other cancer therapies [26,27]. Based on the data showing the CSC phenotype in the chemoresistant cells, we decided to examine the potential of the CSC targeting agents to revert the cisplatin resistance in the NOY-1 CisR cells.…”

Single Cell Transcriptome in Colorectal Cancer—Current Updates on Its Application in Metastasis, Chemoresistance and the Roles of Circulating Tumor Cells

“…(Grillet et al, 2017) subtypes of CRC attain the ability to disrupt drug transport, dysregulate cellular processes, alter drug sensitivity (via genetic or epigenetic modifications) and targets of therapy, that subsequently limit the efficacy of existing anti-cancer therapies (Holohan et al, 2013;Panczyk, 2014;Hu et al, 2016;Zhang and Wang, 2017;Hon et al, 2018;Abu et al, 2019). Since there are hints that metastasis and chemoresistance can be interconnected (Zheng, 2017;Durinikova et al, 2018), the previous can be prevented if chemoresistant subtypes are identified early for optimal or more aggressive treatment. Unfortunately, the mechanisms responsible for chemotherapy resistance by CRC have not been clearly identified.…”

Chemoresistant ovarian cancer enhances its migration abilities by increasing store-operated Ca2+ entry-mediated turnover of focal adhesions

“…Metastasis is intricately linked with resistance to chemotherapy, both clinically and biologically, but the molecular basis for this link is unknown [11][12][13]. Numerous studies have demonstrated that acquired chemoresistance is associated with the metastatic and migratory phenotypes of in human colon adenocarcinoma and ovarian cancer cell lines [14,15]. In our previous study, we demonstrated that chemoresistant ovarian cancer cells acquired epithelial-to-mesenchymal transition (EMT) and stemness phenotype.…”