Metformin’s Role in Colorectal Cancer


Metformin, a widely used anti-diabetic drug, has garnered attention for its potential anti-cancer properties, particularly in colorectal cancer (CRC). This article delves into the intricate mechanisms by which metformin exerts its effects on CRC cells, focusing on miRNA regulation, signaling pathways, and gene expression alterations. By examining the genome-wide impact of metformin exposure and its influence on various signaling pathways, we uncover a detailed picture of how this drug may contribute to cancer treatment.

Understanding How Metformin Helps Fight Colorectal Cancer

Metformin is a common drug used to treat diabetes. Recently, scientists have discovered that it might also help fight colorectal cancer (CRC). This article explains, in simple terms, how metformin works against cancer cells.

How Metformin Works

Metformin changes how cells behave, including cancer cells. When metformin is taken by people with diabetes, it reaches high levels in their intestines, which is where colorectal cancer occurs. Scientists believe this high concentration in the intestines could be why it affects cancer cells so much.

Targeting Cancer Cells

In studies with colorectal cancer cells (specifically a type called HCT116), metformin was found to affect many genes and small molecules called miRNAs. These miRNAs can control how genes work, and by changing them, metformin can slow down or stop cancer cell growth.

Key Findings

  • PI3K-Akt Pathway: Metformin targets a crucial pathway in cancer cells known as the PI3K-Akt pathway. This pathway is important for cell growth and survival. By affecting this pathway, metformin can make it harder for cancer cells to grow and divide.
  • miR-132-3p and miR-2110: These are small molecules that metformin increases in the cancer cells. They help to reduce the activity of a gene called PIK3R3, which is involved in the PI3K-Akt pathway. Reducing PIK3R3 makes it harder for cancer cells to thrive.
  • MAPK/ERK Pathway: Another important pathway affected by metformin is the MAPK/ERK pathway, which controls cell growth and survival. Metformin increases two other small molecules, miR-222-3p and miR-589-3p, which target and reduce a protein called STMN1. This protein is important for cell division, so reducing it helps to slow down cancer cell growth.

Impact on Cancer Cells

When metformin changes these pathways and molecules, it has a big impact on cancer cells:

  • Slows Down Growth: Cancer cells grow and divide more slowly.
  • Stops Division: Cancer cells have a harder time dividing and spreading.
  • Triggers Cell Death: Cancer cells are more likely to die.

Broader Implications

While these studies were done on a specific type of colorectal cancer cell, the findings could be useful for other types of cancer as well. Researchers believe that understanding how metformin affects these pathways and molecules could lead to new treatments for various cancers.

Metformin, a drug commonly used for diabetes, shows promise in fighting colorectal cancer by targeting important pathways and molecules in cancer cells. This makes the cells grow more slowly and die more easily. Researchers are hopeful that these findings will lead to new and better cancer treatments in the future.

In-depth study…..

Metformin’s impact on gene expression is profound. In HCT116 cells, it alters the expression of 1221 mRNAs and 104 miRNAs. These changes in gene expression are crucial as they contribute to tumor progression in the gastrointestinal tract, with varying expression profiles along the gut. Notably, metformin decreases the levels of several oncogenic miRNAs in colorectal cell lines, while increasing others. For instance, Udhane et al. identified 14 differentially expressed (DE) genes involved in intracellular metabolic processes in polycystic ovaries (PCO) through a detailed transcriptome analysis of metformin-associated changes.

In diabetic patients, metformin reaches serum concentrations of approximately 40 µM. However, it accumulates significantly within the intestinal lining, with concentrations up to 300 times higher than those in plasma. This elevated intestinal concentration suggests that metformin’s effects within the intestine may differ from its systemic effects. Our study confirmed that metformin targets components of the PI3K-Akt pathway in HCT116 cells, with unique KEGG pathway signatures highlighting its major molecular targets.

Further validation identified PIK3R3 as a putative target of miR-2110 and miR-132-3p, key regulators of the PI3K-Akt pathway. Both miR-2110 and miR-132-3p were significantly upregulated in metformin-treated HCT116 cells. While miR-132-3p has a well-documented onco-suppressive role, miR-2110, though less studied, has shown specificity to rectal cancer and is associated with tumor development. miR-2110’s pro-differentiation and tumor-suppressive roles have been demonstrated in neuroblastoma, where it induces cell differentiation and reduces cell survival through targeting Tsukushi (TSKU).

In CRC, ectopic expression of miR-132-3p significantly inhibits cell proliferation and invasion, increasing sensitivity to preoperative chemoradiotherapy. It also targets ZEB2, suppressing CRC cell invasion and metastasis. Downregulation of miR-132-3p by DNA hypermethylation correlates with poor prognosis in colorectal cancer. Additionally, miR-132-3p targets Derlin-1 and CREB5, further contributing to its tumor-suppressive effects.

Metformin treatment of HCT116 cells led to a significant increase in miR-132-3p and miR-2110 levels, and a reduction in PIK3R3 expression. The PI3K intracellular signaling pathway, critical for cell apoptosis, cell cycle progression, proliferation, and protein synthesis, plays a definitive role in regulating glucose uptake and metabolism. PI3K dysregulation is common in several cancers, and drugs targeting this pathway are in clinical trials.

Liu et al. confirmed that miR-132-3p directly targets PIK3R3 in hepatocellular carcinoma, showing downregulated PIK3R3 expression in liver cancer tissues and its inverse correlation with tumor differentiation, cancer stage, and lymph node metastasis. In our study, enhanced miR-2110 and miR-132-3p activity led to significant proliferation reduction in six CRC cell lines, decreased PIK3R3 mRNA and protein levels, and suppressed mTOR signal activation in HCT116 cells.

The findings also revealed that metformin affects the MAPK/ERK signaling pathway, which regulates gene expression, cell cycle, metabolism, motility, cell survival, apoptosis, and differentiation. miR-222-3p and miR-589-3p were identified as putative MAPK effectors contributing to the metformin response. While miR-222-3p shows context-dependent bimodal roles in different cancers, its upregulation was noted in glioblastoma, non-small-cell lung cancer, lymphoma, Kaposi sarcoma, and hepatocellular cancer. In contrast, downregulation of miR-222-3p was reported in prostate cancer and AML, where it exerted tumor-suppressive functions.

miR-589-3p’s role in cancer remains less understood, but it has been shown to promote lumbar disc degeneration and suppress cell proliferation, migration, and invasion in glioblastoma cells. STMN1, which encodes stathmin1, a protein regulating microtubule dynamics during mitotic spindle formation, is highly expressed in various cancers and correlates with clinical outcomes in breast cancer, glioma, and hepatocellular carcinoma.

The study showed that metformin treatment in HCT116 cells significantly increased miR-222-3p and miR-589-3p expression, reducing STMN1 gene expression. Exogenous expression of these miRNAs also reduced CRC cell proliferation and STMN1 expression at both mRNA and protein levels. Target protector assays confirmed direct binding and suppression of STMN1 by these miRNAs, highlighting their role in suppressing CRC cell proliferation.

Consistent with previous reports, metformin suppresses CRC cell proliferation by increasing the proportion of cells in the G1 phase. Our study confirmed that increased miR-132-3p, miR-2110, miR-589-3p, and miR-222-3p activities delay the cell cycle at the G1 phase, partly due to direct transcript binding and downregulation of PIK3R3 or STMN1. These miRNAs, prevalent in various cancers, emerge as central players influenced by metabolic regulation.

While the initial transcriptomic analysis focused on a specific CRC cell line with microsatellite instability, the findings were validated across various CRC cell lines with differing genotypes. This replication enhances the robustness and reliability of our results, underscoring the generalizability of the identified mechanisms.

A notable limitation of our study is the use of a high-glucose medium, which does not fully represent the physiological nutrient environment encountered by cells in vivo. Replicating our experiments with media resembling physiological nutrient levels would better mimic in situ tumor conditions.

The results, combined with previous studies, conclude that metformin exerts its anti-cancer properties by inducing miRNAs such as miR-2110, miR-132-3p, miR-222-3p, and miR-589-3p to target genes including PIK3R3 and STMN1. This regulation affects signaling pathways like PI3K-Akt and MAPK/ERK, highlighting the potential for developing RNA therapeutics. Further investigations are needed to elucidate the clinical implications and therapeutic opportunities stemming from these discoveries, paving the way for targeted interventions in CRC management.

Metformin has proven anti-cancer properties, reprogramming cancer cell metabolism. Its mechanisms of action include activating AMPK, inhibiting the mTOR pathway, regulating inflammatory responses, and promoting cancer stem cell death. The inhibitory effects of metformin on CRC have been reported at the pre-clinical level, leading to clinical trials evaluating its combination with standard chemotherapeutics.

Combining chemotherapeutics with metformin shows additive responses, targeting numerous pathways affecting tumorigenesis and progression. However, the molecular mechanisms and crosstalk between signaling pathways contributing to metformin’s anti-cancer effects remain elusive. Phosphatidylinositol-3-kinase (PI3K)/AKT signaling is a master regulator for cancer, and the MAPK/ERK pathway plays a key role in cellular responses to extracellular signals.

Evidence confirms that several miRNA changes are associated with metformin’s anti-proliferative activity. Metformin treatment alters miRNA expression in hepatocellular carcinoma, pancreatic cancer, oesophageal squamous cancer, gastric cancer, lung cancer, and prostate cancer. These miRNA alterations likely result in functional changes in gene expression, necessitating an integrated-systems biology approach to understand transcriptional and post-transcriptional responses to metabolic disruption in CRC.

This study provides a comprehensive snapshot of metformin treatment-associated changes in HCT116 cells, using small RNA sequencing and transcriptome analyses. It characterizes metformin response pathways across different CRC cell lines, identifying specific miRNA–target transcript interactions contributing to the metformin response in colorectal cancer cells.

Overall, metformin’s ability to modulate key signaling pathways and miRNA expression profiles highlights its potential as a therapeutic agent in CRC treatment. Future research should focus on elucidating the broader implications of these findings and exploring novel therapeutic avenues based on these insights.

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