What are Biochemical Pathways?
Biochemical pathways are a series of chemical reactions occurring in a living system.
Biochemical pathways or metabolic pathways are a step by step series of interconnected biochemical reactions in which each step is catalyzed by a specific enzyme. (catalyzed definition: an agent that provokes or speeds significant change or action). During the series of chemical reactions, the substrate is converted into a product that in turn acts as a substrate for a subsequent reaction. So, a molecule or substrate are being continuously converted into metabolic intermediates eventually yielding a final product.
Cells are the basic units of living organisms and cells operate through the biochemical reactions that take place within the cell. Reactions are turned on and off or sped up and slowed down according to the cell’s immediate needs and overall functions. At any given time, the numerous pathways involved in building up and breaking down cellular components must be monitored and balanced in a coordinated way. To achieve this goal, cells organize reactions into various enzyme-powered pathways.
There are around 1300 enzymes found in the human cell and each of these enzymes are coded by a different gene. Metabolism takes place when these enzymes work synchronously resulting in chemical reactions taking place at the rate of 37 thousand billion times per second in the human body. Enzymes play a critical role as they are the only ones who are capable of making small minute changes to a molecular layer by either breaking a bond or making a bond.
The types of biochemical pathways are anabolic pathways, catabolic pathways and amphibolic pathways. Anabolic enzymes catalyse chemical reactions in which bonds are formed and catabolic enzymes that catalyse chemical reactions in which bonds are broken, anabolic is both (think of someone who is ambidextrous, equally left and right handed).
There are complex ways by which the metabolic pathways are regulated. Reactions are turned on and off or sped up and slowed down according to the cell’s immediate needs and overall functions. Enzymes are protein catalysts that speed biochemical reactions by facilitating the molecular rearrangements that support cell function. Cell function depends on this continual uptake and conversion of energy.
What are Signaling Pathways?
These pathways involve a series of chemical reactions in which a group of molecules in a cell work together to control a cell function, such as cell division or cell death. A cell receives signals from its environment when a molecule, such as a hormone or growth factor, binds to a specific protein receptor on or in the cell. After the first molecule in the pathway receives a signal, it activates another molecule. This process is repeated through the entire signaling pathway until the last molecule is activated and the cell function is carried out. Abnormal activation of signaling pathways may lead to diseases, such as cancer.
The Suppression-centric anticancer strategy SCANS aims to manipulate specific molecules involved in these pathways to stop cancer cells from growing.
10 Biochemical pathways that some cancer cells use to grow
Triple negative breast cancer and other cancer types exploit these ten pathways.
- HIF-1hypoxic factor
- Hedgehog canonical signaling pathway
- MAPK pathway
- MTAP used for polyamine synthesis
- NF-κB signaling pathway
- Notch pathway (Ligands: Jagged1, Jagged2, and
δ-like ligand 1, 3, and 4) - PI3K/Akt/mTOR signaling pathway
- p53 and POLR2A gene expression
- STAT3 signaling pathway
- Wnt/ β-catenin pathway
The following information is published in the Review Paper by Webb and Kukard 2020 and supporting references within can be accessed from the free download at the Journal site. I have included some of the breast cancer related information to give you some contextual framework.
HIF-1hypoxic factor
Parts of hypoxic tumors have lower oxygen concentrations than healthy tissue. This hypoxic tumor environment selects more for a malignancy with increased mutation rates, evasion of apoptosis (programmed cell death), cell proliferation and less drug permeability. HIF-1 has a dominant role in the response to acute hypoxia and HIF-2 in chronic hypoxia in solid cancer tumors. HIF-1 regulates transcription of genes encoding glycolytic pathway enzymes, for example, Lactate dehydrogenase exhibits oxygen dependent regulation.
Hedgehog canonical signaling pathway
The Hedgehog/ glioma-associated oncogene pathway is a signaling cascade fundamental for functions in vertebrate embryogenesis and adult tissue homeostasis. During evolution the Hedgehog pathway has diverged and intermeshed with other signaling pathways to control cell growth and patterning.
MAPK pathway aka Ras-Raf-MEK-ERK pathway
The Mitogen Activated Protein Kinases pathway (MAPK) is also known as the Ras-Raf-MEK-ERK pathway. It is a chain of proteins within the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. Short transient receptor potential channel 3 (TRPC3) which is part of this pathway has been found to regulate the proliferation and apoptosis resistance in TNBC cells.
MTAP used for polyamine synthesis.
Polyamines are organic compounds having more than 2 amino acid groups. They interact with negatively charged particles such as DNA, RNA and proteins
and influence cell growth, survival, and proliferation. Synthesis of polyamines occurs in the cytoplasm of cells in all tissues from the amino acids: L-methionine and L-ornithine (amino acid produced via the urea cycle and not found in proteins). Due to their rapid growth, cancer cells require
larger quantities of nutrients such as amino acids and glucose than non-cancerous cells. Methionine dependence in cancer cells may be a result of deletions, polymorphisms or alterations in expression of genes in the methionine de novo and salvage pathways. These defective cancer cells are
unable to regenerate methionine via these pathways. A byproduct of polyamine synthesis is methylthioadenosine MTA). MTA is broken down by the enzyme, methylthioadenosine phosphorylase (MTAP) and is a step in the salvage of methionine. All normal mammalian tissues contain MTAP. Methylthioadenosine phosphorylase is encoded by the MTAP gene. Polyamine content is increased in many cancers arising from epithelial tissues such as skin,
colon, and breast. The ductal or luminal cells of the breast are specialized epithelial cells. Cancer cells require much more methionine than normal cells. Methionine deprivation in hormone receptor breast cancer cells reduces growth of tumor-initiating cells. Cancer cells cannot produce enough polyamine in methionine restricted diets.
The MTAP gene encodes an enzyme involved in polyamine metabolism. Cancers that lose MTAP expression need methionine and fail to grow when deprived of it. Loss of MTAP expression from the methionine salvage pathway is a major factor of methionine dependence in cancer and MTAP itself may act as a tumor suppressor.
Methionine is in proteins and is highest in fish, beef, dairy, eggs, nuts, seeds, and grains.
NF-κB Signaling pathway
Members of the transcription factor nuclear factor kappa-light chain enhancer of activated B cells (NF-κB) family activate a rapid progression of gene expression and play a primary role in various responses leading to host defense such as the immune response. NF-κB regulates the expression in TNBC cells of the cell surface glycoprotein known as CD44. CD44 is involved in cell adhesion, migration and proliferation and suppression via NF-κB inhibition decreased proliferation and invasiveness.
Notch pathway
The Notch signaling pathway is a highly conserved and evolutionarily ancient cell signaling system present in most animals. It affects the instigation of differentiation, proliferation, and apoptotic programs, providing overall developmental influence on organ formation and morphogenesis. Notch regulates TNBC mitochondrial activity, stimulates P13K/AKT phosphorylation (see below), oxidative metabolism and transcription of survival genes in PTEN wild-type TNBC cells.
PI3K/Akt/mTOR pathway
The phosphatidylinositol 3-kinase (PI3K) and Akt/Protein Kinase B (PI3K) signaling
pathway includes of multiple proteins/enzymes such as mTOR and Akt. The main mediator of the PI3K signaling pathway, Akt, is phospho-activated by either PDK-1 or mTOR. Akt positively controls cyclin D1, negatively regulates cyclin-dependent kinase inhibitors (CKIs) p21 and p27, and primes the G1/S of cell-cycle transition, driving oncogenic growth.
p53 gene, POLR2A suppression & MDM2 oncogene
The Tumor Protein (p53) gene is a tumor suppressor gene stopping the formation of tumors. Over 50% of human tumors contain a mutation or deletion of the p53 gene. This gene is the most frequently mutated or missing gene in TNBC; another gene, POLR2A is closely related. The p53 tumor suppressor protein is short-lived and its levels are controlled by mouse double minute 2 homolog (MDM2) protein. The regulation process involves binding of the MDM2 protein to the transactivation domain (defined by: transcription factor scaffold domain which contains binding sites for other proteins) of p53 which is followed by ubiquitination (defined by: small regulatory protein) and rapid turnover of p53.
Stat3 signaling pathway
Human cancers can be initiated, and progression promoted by the Signal Transducer and Activator of Transcription (STAT) protein family via inhibiting apoptosis and inducing cell proliferation, angiogenesis, invasion and metastasis. The suppression of STAT3 activation results in apoptosis in tumor cells. A human clinical trial of a STAT3 inhibitor shows modest efficacy against advanced unselected tumors. The transcriptional protein STAT3 has heterogeneous functions controlling tumor microenvironments but studies specific to breast cancer and TNBC suggest STAT3 is necessary for these tumors to thrive. STAT3 is overexpressed and activated in TNBC and is highly related to TNBC initiation, progression, metastasis, resistance to chemotherapy, and poor survival outcomes. STAT3 appears to be involved in the regulation of invasion mechanisms in TNBC and prometastatic gene signatures in a TNBC subtype specific manner. Standard treatments for TNBC do not currently target the STAT3 signaling pathway.
Wnt/β-catenin pathway (Wnt ligand)
The Wnt/β- catenin pathway (Wnt ligand) (WNT) signaling pathway regulates cancer stem cell (CSC) activity, promoting tumor progression and distant metastasis in breast cancer. The protein Cadherin 11 (CDH11) is overexpressed in invasive breast cancer cells and involved in distant bone metastases in numerous other cancers. Growing evidence suggest that cadherins play critical roles in WNT signaling pathway. Signaling Cadherin regulates the canonical WNT signaling pathway inhibiting the CSC-like metastatic phenotypes and tumor growth of TNBC cells.