1. Combination of miR-143 and miR-506 reduces lung and pancreatic cancer cell growth through the downregulation of cyclin-dependent kinases
- Author
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Gerardo G. Mackenzie, George Mattheolabakis, and A K M Nawshad Hossian
- Subjects
Cancer Research ,Lung Neoplasms ,Cell ,pancreatic cancer ,Aminopyridines ,Piperidines ,2.1 Biological and endogenous factors ,Aetiology ,Lung ,Cancer ,Tumor ,biology ,Chemistry ,Cell Cycle ,General Medicine ,Articles ,Cell cycle ,Cyclin-Dependent Kinases ,Up-Regulation ,medicine.anatomical_structure ,Oncology ,cell cycle ,Oncology and Carcinogenesis ,Down-Regulation ,miR‑506 ,Antineoplastic Agents ,Cell Growth Processes ,Transfection ,Cell Line ,miR‑143 ,Rare Diseases ,Cyclin-dependent kinase ,Cell Line, Tumor ,CDC2 Protein Kinase ,Genetics ,medicine ,Humans ,Flavonoids ,Cyclin-dependent kinase 1 ,Oncogene ,Cell growth ,miR-506 ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Fibroblasts ,medicine.disease ,miR-143 ,Pancreatic Neoplasms ,lung cancer ,MicroRNAs ,Apoptosis ,Purines ,biology.protein ,Cancer research ,Digestive Diseases - Abstract
Lung cancer (LC) and pancreatic cancer (PC) are the first and fourth leading causes of cancer‑related deaths in the US. Deregulated cell cycle progression is the cornerstone for rapid cell proliferation, tumor development, and progression. Here, we provide evidence that a novel combinatorial miR treatment inhibits cell cycle progression at two phase transitions, through their activity on the CDK4 and CDK1 genes. Following transfection with miR‑143 and miR‑506, we analyzed the differential gene expression of CDK4 and CDK1, using qPCR or western blot analysis, and evaluated cell cycle inhibition, apoptosis and cytotoxicity. The combinatorial miR‑143/506 treatment downregulated CDK4 and CDK1 levels, and induced apoptosis in LC cells, while sparing normal lung fibroblasts. Moreover, the combinatorial miR treatment demonstrated a comparable activity to clinically tested cell cycle inhibitors in inhibiting cell cycle progression, by presenting substantial inhibition at the G1/S and G2/M cell cycle transitions. More importantly, the miR‑143/506 treatment presented a broader application, effectively downregulating CDK1 and CDK4 levels, and reducing cell growth in PC cells. These findings suggest that the miR‑143/506 combination acts as a promising approach to inhibit cell cycle progression for cancer treatment with minimal toxicity to normal cells.
- Published
- 2021