RXRα Gene
The nuclear receptor family of transcription factors, which includes the RXR gene, is crucial for controlling cell proliferation, differentiation, and death. According to studies, berberine can control RXR expression, which can alter cellular communication and gene expression and prevent the formation of cancer.
One such gene that has been discovered to be controlled by berberine is the retinoid X receptor alpha (RXR) gene, which is known to be involved in cancer. According to studies, berberine can activate the RXR in cancer cells, which inhibits growth of cancer cell and apoptosis [1].
2. MMPs Gene
The extracellular matrix and basement membrane components, which allow cancer cells to penetrate and spread to other organs, are broken down by a family of zinc-dependent enzymes called MMPs. Berberine has demonstrated promising anticancer benefits, such as reducing cancer cell growth and causing apoptosis.
More significantly, berberine can control the expression of matrix metalloproteinases (MMPs), which is crucial for the invasion and metastasis of cancer. Studies show that berberine targets the MAPK signaling pathway, which is essential for MMP production, and as a result, can lower MMP 2 & 9 expression [2].
3. AMPK Gene
It is a cellular energy-sensing mechanism that, through phosphorylation, initiates several downstream signaling cascades. Many malignancies have dysregulated mTORC1 signaling, which promotes cancer cell proliferation and confers resistance to treatment. The use of berberine in cancer treatment is growing. It has been discovered to stop the cell cycle, trigger apoptosis, and prevent the spread of cancer cells through invasion and metastasis.
Additionally, research has demonstrated that Berberine can control the AMPK pathway, which is crucial for controlling cellular energy homeostasis, including glucose and lipid metabolism, autophagy, and immune response. The deregulation of the AMPK pathway has been related to the development and progression of many forms of cancer [3].
4. PPARγ Gene
One of the most well-investigated ligand-inducible transcription factors is PPARγ. It is a nuclear receptor that controls several physiological functions, such as cell differentiation, metabolism, and inflammation. The gene is overexpressed in several cancer types. A higher risk of cancer formation and progression is linked to this overexpression. Nevertheless, a variety of compounds, including berberine, have been shown to regulate PPAR Gamma expression, halting the multiplication and growth of cancer cells.
Berberine was shown to downregulate the expression of PPAR gamma. Moreover, it has been demonstrated that berberine blocks PPAR Gamma's tumor-promoting functions, reducing the likelihood of the development and spread of cancer [4].
5. P53 Gene
The P53 gene produces a protein that is present in the cell nucleus and is essential for regulating cell division and cell death. The P53 gene, also known as the genome's guardian, controls how quickly and how many times cells divide. P53 gene mutations impair a cell's ability to function normally, causing uncontrolled cell proliferation and the emergence of cancer. The P53 gene in healthy cells activates the cellular machinery to either repair DNA damage or cause cell death when there is damage. As a result, research suggests that upregulating P53 expression may be a useful cancer prevention tactic.
Recent research has demonstrated that the active component of many medicinal herbs, berberine, may control the P53 gene's expression. It may help to prevent several types of cancer by inducing cellular death in a P53-dependent way. Berberine prevents cancer cells from proliferating, stops the cell cycle, and even triggers apoptosis unique to cancer cells. So, the prospect of berberine being used as a potent anti-cancer substance is quite exciting.
Berberine has numerous ways by which it can influence the P53 gene expression. Specifically, the molecular processes implicated in berberine’s action on P53 include lowering the degradation of P53, boosting its transcriptional activity, and maintaining its conformational shape. These mechanisms promote P53’s tumor suppressor activity and inhibit cancer cell growth [5].
6. NF-κB Gene
A transcription factor known as nuclear factor-B is essential for several biological functions, such as immune response, inflammation, cell growth and survival, and development. Several inflammatory triggers, including growth hormones and pathogenic microorganisms, activate NF-B.
According to research, berberine can stop NF-B from activating by blocking it from entering the nucleus. The suppression of the upstream signaling events that activate the NF-B pathway is the mechanism by which this inhibition is mediated. For instance, berberine can reduce the activity of IB kinase, which is in charge of phosphorylating and degrading IB, a crucial NF-B inhibitor [6].
7. Mdr1 Gene
Mdr1 is a multiple drug resistance transporter gene which encodes a transporter protein called pgp-170. The Mdr1 gene, also known as ABCB1, is responsible for encoding a protein called P-glycoprotein. It is an efflux pump that helps to remove toxins, drugs, and other foreign substances from the body. It is also often found to be overexpressed in cancer cells, leading to multidrug resistance and decreased effectiveness of chemotherapy.
Understanding the role of the Mdr1 gene and P-gp in cancer can help in the development of new treatments for cancer patients with drug-resistant tumors. Many studies have shown its role in gastrointestinal disorders and cancer. Targeting the Mdr1 gene was shown to be successful with berberine [7].
8. PCSK9 Gene
Proprotein convertase subtilisin / kexin type 9 is a gene which participates in the regulation of cholesterol in the blood by catabolism. It degrades the LDL receptor protein in response to the level of cholesterol in the blood. It was shown in a study that berberine HCL inhibited the PCSK9 gene as a result LDL cholesterol level was decreased.
Additionally, studies have demonstrated a connection between berberine's anti-cancer capabilities and its capacity to control PCSK9 gene expression. On a variety of cancer cells, berberine has been discovered to exhibit anti-tumor properties. For instance, berberine was found to drastically reduce the proliferative capacity of human leukemia cells by inhibiting PCSK9-mediated signaling pathways in recent research [8].
9. AKT Gene
The AKT gene codes for the production of the AKT1 kinase protein. This protein is found in a variety of cell types throughout the body and is essential to several signaling pathways.
Many cancer types frequently have increased AKT expression or activation, which is linked to a bad prognosis. Berberine can inhibit the AKT pathway, reducing tumor size and increasing apoptosis, according to some studies (cell death). By specifically targeting the AKT gene and lowering its expression and activity, berberine produces this effect. Additionally, it blocks the activity of AKT which prevents cancer cells from proliferating and results in cell death [9].
10. CDK Genes
CDK, a cyclin-dependent family of protein kinases known as cyclin-dependent kinases was initially identified as a means of controlling the cell cycle. Moreover, they control mRNA processing, transcription, and nerve cell differentiation. One of the most important CDKs is CDK2 and CDK9 which regulate the cell cycle.
The role of CDKs in cancer is well known as any disruption or mutation in these genes will lead to the irregular control of the cell cycle and leads to cancer. By the inhibition of several CDKs in cancer cells, berberine has been demonstrated to cause G1 arrest of the cell cycle [10].
11. CYC1 Gene
Cytochrome c is an electron carrier which transports electrons from complex 3 to complex 4 in the mitochondria during the oxidative electron transport chain.
When it is released from the mitochondria through the permeability pore it causes apoptosis. CYC1 is linked to causing cancer as it is associated with initiating apoptosis. Many studies have shown that berberine can downregulate the expression of CYC1 and also inhibit its release from the mitochondria by targeting BAX and BAK proteins to impart its anti-cancer effect [11].
12. CASP Genes
The family of proteins known as caspases (CASP) carries the mechanism of programmed cell death and is implicated in apoptosis. Caspases come in two varieties: initiator caspases, which start the apoptosis process, and executioner caspases, which continue to control it.
Three executioner caspases are 3, 8, and 9. Apoptosis and caspases are crucial processes in cancer cells. To help cancer cells avoid apoptosis, the expression of these CASP genes is suppressed and downregulated in cancer cells. In many clinical studies, it was shown that berberine can upregulate the expression of CASP genes and decrease tumor size [12].
13. AP1 Gene
AP-1 gene, which is essential for the emergence and spread of cancer. A transcription factor known as AP-1 is related to tumor development, invasion, metastasis, and treatment resistance and is increased in some malignancies.
The proliferation, migration, invasion, and treatment resistance of cancer cells is all inhibited as a result of the downregulation of AP-1. Berberine has also been demonstrated to suppress AP-1 expression in cancer cells, leading to apoptosis. Berberine decreases AP-1's stability and prevents it from attaching to DNA in cancer cells, hence limiting AP-1 function [13].
14. IFN1B Gene
IFN-β1 gene, which is essential for both cancer growth and immune response. IFN-β1, a cytokine linked to tumor development, metastasis, and treatment resistance, is increased in response to viral infection.
Some cancer cells, including colon and liver cancer cells, have been found to produce more IFN-β1 when berberine is present. This increase in IFN-β1 inhibits cancer cells, which sets off the immune system's response to them. Also, it has been shown that berberine increases the production of IFN-β1 in cancer cells, making them more sensitive to chemotherapy and radiation. The activity of STAT3, a transcription factor that suppresses the production of IFN-β1 in cancer cells, is also decreased by berberine, it has been shown [14].
15. HIF 1A Gene
The hypoxia-inducible factor 1-alpha gene is crucial for the onset and progression of cancer. HIF-1 is a transcription factor that is elevated in some malignancies and is associated with tumor formation, angiogenesis, metastasis, and treatment resistance.
The expression of HIF-1 is downregulated by berberine in many cancer cells. Moreover, it has been shown that berberine inhibits HIF-1 expression in cancer cells, causing those cells to undergo apoptosis. Also, it has been found that berberine decreases the stability of HIF-1 and prevents it from binding to DNA in cancer cells, both of which are known to diminish HIF-1 function [15].
16. TNF Alpha Gene
Proinflammatory cytokine tumor necrosis factor alpha has a significant role in the etiology of several illnesses. TNF alpha is a cytokine that is increased in some malignancies and is linked to metastasis, tumor development, and medication resistance.
Berberine reduces the expression of TNF alpha in some cancer cells, including pancreatic, liver, and breast cancer cells. The downregulation of TNF alpha prevents the proliferation, migration, invasion, and treatment resistance of cancer cells. Berberine has also been demonstrated to suppress TNF alpha expression, which causes apoptosis in cancer cells. Also, it has been shown that berberine prevents cancer-associated macrophages, which are essential for the development and spread of tumors, from secreting TNF alpha [16].
17. VEGFA Gene
VEGFA is a cytokine that has been linked to a poor prognosis and is upregulated in some cancers. This gene, which belongs to the VEGF family, produces a protein that is frequently discovered as a disulfide-connected homodimer. This glycosylated mitogen protein has a variety of actions on endothelial cells, including mediating enhanced vascular permeability, stimulating angiogenesis, vasculogenic, and endothelial cell development, encouraging cell migration, and suppressing apoptosis.
It has been discovered that berberine inhibits the expression of VEGFA in a variety of cancer cells. Berberine has also been demonstrated to suppress VEGFA expression in cancer cells, leading to the induction of apoptosis. Also, it has been shown that berberine reduces the production of VEGFA in cancer-associated fibroblasts (CAFs), which are crucial for tumor angiogenesis and proliferation [17].
18. GDF15 Gene
The SMAD family of transcription factors, which regulate gene expression, are attracted to and activated as a result of the GDF 15 class of ligands binding to TGF-beta receptors. When it is increased, the cytokine GDF15 is linked to drug resistance, metastasis, and tumor growth in some cancers.
It has been found that berberine suppresses GDF15 expression in a range of cancer cells. This downregulation of GDF15 prevents cancer cells from proliferating, migrating, and invading. Also, it has been demonstrated that berberine lowers GDF15 expression in cancer-associated fibroblasts (CAFs), which are essential for the growth and dissemination of tumors [18].
19. EGFR Gene
Epidermal growth factor receptor is a gene which encodes a protein which is a receptor present on the cell surface. The expression of EGFR and its ligands, such as TGF-alpha and EGF, is inhibited by berberine in a range of cancer cells.
It has been shown that berberine inhibits the activity of STAT3, a TF that is crucial for the development of cancer [19].
20. BCL Genes
Apoptosis is regulated by BCL family proteins. The B-cell lymphoma (BCL) gene family is crucial in controlling apoptosis. It has been shown that berberine alters the expression of BCL genes in cancer cells, causing apoptosis to be induced and inhibiting tumor development. Moreover, berberine has been discovered to control the expression of the BCL gene, which makes cancer cells more susceptible to chemotherapy medicines [20].
Comments