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A functional screen with metformin identifies microRNAs that regulate metabolism in colorectal cancer cells
Ayla Orang1, Saira R Ali1, Janni Petersen1
1Flinders Health and Medical Research Institute - Cancer Program, Flinders University, Adelaide, South Australia, 5042, Australia.
Abstract:
Metformin inhibits oxidative phosphorylation and can be used to dissect metabolic pathways in colorectal cancer (CRC) cells. CRC cell proliferation is inhibited by metformin in a dose dependent manner. MicroRNAs that regulate metabolism could be identified by their ability to alter the effect of metformin on CRC cell proliferation. An unbiased high throughput functional screen of a synthetic micoRNA (miRNA) library was used to identify miRNAs that impact the metformin response in CRC cells. Experimental validation of selected hits identified miRNAs that sensitize CRC cells to metformin through modulation of proliferation, apoptosis, cell-cycle and direct metabolic disruption. Among eight metformin sensitizing miRNAs identified by functional screening, miR-676-3p had both pro-apoptotic and cell cycle arrest activity in combination with metformin, whereas other miRNAs (miR-18b-5p, miR-145-3p miR-376b-5p, and miR-718) resulted primarily in cell cycle arrest when combined with metformin. Investigation of the combined effect of miRNAs and metformin on CRC cell metabolism showed that miR-18b-5p, miR-145-3p, miR-376b-5p, miR-676-3p and miR-718 affected glycolysis only, while miR-1181 only regulated CRC respiration. MicroRNAs can sensitize CRC cells to the anti-proliferative effects of metformin. Identifying relevant miRNA targets may enable the design of innovative therapeutic strategies.
Insights
Metformin, a drug that inhibits oxidative phosphorylation, can be utilized to study colorectal cancer (CRC) metabolism. Researchers identified specific microRNAs (miRNAs) that enhance metformin's anti-cancer effects by impacting CRC cell proliferation and metabolism.
Area of Science:
- Oncology
- Molecular Biology
- Metabolism
Background:
- Metformin is known to inhibit oxidative phosphorylation and affect colorectal cancer (CRC) cell proliferation.
- MicroRNAs (miRNAs) play crucial roles in regulating cellular metabolism and could potentially modulate the response to metformin in CRC.
Purpose of the Study:
- To identify miRNAs that impact the metformin response in CRC cells using a high-throughput functional screen.
- To investigate how these identified miRNAs affect CRC cell proliferation, apoptosis, cell-cycle, and metabolism in combination with metformin.
Main Methods:
- Conducted an unbiased high-throughput functional screen of a synthetic miRNA library to identify miRNAs affecting metformin response in CRC cells.
- Performed experimental validation on selected miRNA hits to confirm their effects on CRC cell proliferation, apoptosis, cell-cycle, and metabolism.
- Analyzed the impact of combined miRNA and metformin treatment on CRC cell glycolysis and respiration.
Main Results:
- Identified eight miRNAs that sensitize CRC cells to metformin.
- miR-676-3p demonstrated both pro-apoptotic and cell cycle arrest activity with metformin.
- Other identified miRNAs (miR-18b-5p, miR-145-3p, miR-376b-5p, miR-718) primarily induced cell cycle arrest and affected glycolysis, while miR-1181 impacted CRC respiration.
Conclusions:
- MicroRNAs can sensitize colorectal cancer cells to the anti-proliferative effects of metformin.
- The identified miRNAs modulate CRC cell proliferation, apoptosis, cell-cycle, and metabolism.
- Targeting these miRNAs could lead to novel therapeutic strategies for colorectal cancer treatment.
