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Forced Overexpression and Knockout Analysis of SLC30A and SLC39A Family Genes Suggests Their Involvement in
Margarita Kamynina1, Julian M Rozenberg2, Artem S Kushchenko3
1World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov First Moscow State Medical University, 119991 Moscow, Russia.
Abstract:
The metabolism of zinc and manganese plays a pivotal role in cancer progression by mediating cancer cell growth and metastasis. The SLC30A family proteins SLC30A3 and SLC30A10 mediate the efflux of zinc, manganese, and probably other transition element ions outside the cytoplasm to the extracellular space or into intracellular membrane compartments. The SLC39A family members SLC39A8 and SLC39A14 are their functional antagonists that transfer these ions into the cytoplasm. Recently, the SLC30A10 gene was suggested as a promising methylation biomarker of colorectal cancer. Here, we investigated whether forced overexpression or inactivation of SLC30A and SLC39A family genes has an impact on the phenotype of cancer cells and their sensitivity to cancer therapeutics. In the human colon adenocarcinoma HCT-15 and duodenal adenocarcinoma HuTu80 cell lines, we generated clones with knockouts of the SLC39A8 and SLC39A14 genes and forced overexpression of the SLC30A3, SLC30A10, and SLC39A8 genes. Gene expression in the mutant and control cells was assessed by RNA sequencing. The cell growth rate, mitochondrial activity, zinc accumulation, and sensitivity to the drugs cetuximab and cisplatin were investigated in functional tests. Overexpression or depletion of SLC30A or SLC39A family genes resulted in the deep reshaping of intracellular signaling and provoked hyperactivation of mitochondrial respiration. Variation in the expression of the SLC30A/SLC39A genes did not increase the sensitivity to cetuximab but significantly altered the sensitivity to cisplatin: overexpression of SLC30A10 resulted in an ~2.7-4 times increased IC50 of cisplatin, and overexpression of SLC30A3 resulted in an ~3.3 times decreased IC50 of cisplatin. The SLC30A/SLC39A genes should be considered as potential cancer drug resistance biomarkers and putative therapeutic targets.
Insights
Altering zinc and manganese transporter genes (SLC30A/SLC39A) impacts cancer cell behavior and drug sensitivity. These genes are potential biomarkers for cancer drug resistance and therapeutic targets.
Area of Science:
- Molecular Biology
- Cancer Research
- Cellular Metabolism
Background:
- Zinc and manganese metabolism are crucial in cancer progression.
- SLC30A and SLC39A gene families regulate metal ion transport.
- SLC30A10 is a potential colorectal cancer methylation biomarker.
Purpose of the Study:
- To investigate the impact of SLC30A and SLC39A gene manipulation on cancer cell phenotype and drug sensitivity.
- To explore the role of metal ion transporters in cancer therapeutics.
Main Methods:
- Generated gene knockout and overexpression cell lines (HCT-15, HuTu80).
- Utilized RNA sequencing for gene expression analysis.
- Performed functional assays on cell growth, mitochondrial activity, zinc accumulation, and drug sensitivity (cetuximab, cisplatin).
Main Results:
- Gene manipulation reshaped intracellular signaling and hyperactivated mitochondrial respiration.
- Altered SLC30A/SLC39A expression did not affect cetuximab sensitivity.
- Overexpression of SLC30A10 increased cisplatin IC50, while SLC30A3 overexpression decreased it.
Conclusions:
- SLC30A/SLC39A gene expression significantly influences cancer cell response to cisplatin.
- These genes represent potential biomarkers for cancer drug resistance.
- SLC30A/SLC39A genes are putative therapeutic targets in cancer treatment.
