Chapter 8: Apoptosis and Cancer - PDF

Chapter 8: Apoptosis and Cancer Outline: The role of p53 Apoptosis Basic properties of a cancer cell Causes of cancer Genetics of cancer Strategies of combating cancer 1. p53: Guardian of our Genome p53 transcription factor ○ Key protein in mammalian cell’...

Chapter 8: Apoptosis and Cancer Outline: The role of p53 Apoptosis Basic properties of a cancer cell Causes of cancer Genetics of cancer Strategies of combating cancer 1. p53: Guardian of our Genome p53 transcription factor ○ Key protein in mammalian cell’s response to stress ○ Synthesized in response to stress ○ Key player on how we respond to the stress of the day ○ Manages the necessary transcription factors to be synthesized to face the stress Normal cells ○ Very low activated p53 ○ Must be phosphorylated and acetylated to be activated Addition of a phosphate group always activates something Damaged DNA causes p53 to be activated by kinases and acetylases Mdm2 keeps the activity of p53 low Activated p53 is released from mdm2 when DNA is damaged Once DNA is damaged, p53 has choices ○ Apoptosis First decision that p53 will opt for ○ Prior to apoptosis, there are several mechanisms to repair DNA Cell cycle arrest Halts cell cycle if there is damage or something wrong p53 mediates apoptosis p53 - directs genetically damaged cell to apoptosis 2. Apoptosis: a normal occurrence Programmed cell death John Kerr ○ 1972 ○ University of Aberdeen, Scotland ○ C. elegans (nematode) 1st molecular study of apoptosis Mouse liver apoptotic cells in the image ○ White spaces since the cells are shrinking Characteristics of cells undergoing apoptosis: ○ Cell and nucleus shrink ○ Loss of adhesion to neighboring cells ○ Blebs on cell surface ○ Chromatin is fragmented p53 decides which cells should undergo apoptosis Skin squamous cells ○ Top Stomach ○ Bottom Importance of apoptosis ○ Maintains homeostasis ○ Eliminates cells with irreparable DNA damage Apoptosis occurs in less than one hour ○ Cells shrink away from neighbors ○ Apoptotic bodies with phosphatidylserine at outer membrane Phosphatidylserine is recognized as “eat me” signal by macrophages Extrinsic and intrinsic pathways of apoptosis Extrinsic Pathway ○ External stimuli ○ Extracellular messenger binds to its receptor → activated receptor binds to → 2 cytoplasmic adaptor proteins (FADD & TRADD) and procaspase-8 → form a multiprotein complex → FADD and TRADD interact at death domains → procaspase-8 & FADD interact at death effector domains → active caspase-8 carries out death sentence procaspase-8 Fore-runner Precursor of caspase ○ Caspases are molecules that execute the death of cells Intrinsic Pathway Internal stimuli What triggers intrinsic apoptosis? ○ Irreparable DNA damage ○ Lack of O2 (hypoxia) ○ High cytosolic Ca2+ (F actin aggregates in endothelial cells) ○ Severe oxidative stress Destructive free radicals Imbalance between ROS and ability to detoxify ○ Pathway Stressful stimuli → activate Bax → moves from cytosol to outer mitochondrial membrane → release of cyctochrome c → cyctochrome c + cytosolic Apaf-1 protein + procaspase-9 to form apoptosome → caspase-9 cleaves → activates executioner caspases → apoptosis Free Radicals or ROS and Antioxidant Any reactive organic or inorganic molecule with an odd number of electrons resulting in a species with one unpaired electron If the level of free radicals is higher than antioxidants, it will cause oxidative stress Generic name: ○ Reactive Oxygen Species ROS and Examples Highly reactive chemicals formed from: ○ Oxygen (O2) ○ Water ○ Hydrogen peroxide Examples: ○ Hydroxyl radical ○ Hydroperoxide (O2H) ○ Singlet oxygen Dual Roles of ROS Turns on and off biological functions Intrinsic to cellular functioning Causes cell damage, genetic mutations and aging Cumulated ROS leads to oxidative stress Anti-oxidants Protect cells from damage by free radicals Example ○ beta-carotene ○ lycopene ○ Vitamin A, C, E (tocopherol) Vitamin E Eggs Meat Cereal Fruits Vegetable oil Bcl2 family: Bax and Bcl2 p53 activates bax-bax homodimer → apoptosis Bax-Bcl2 heterodimer → normal cell Increased Bcl2 → activates oncogene 3. Basic Properties of Cancer Cells Cancer: Loss of Growth Control Inherited disease ○ Alterations within specific gene Not an inherited disease (mostly) ○ DNA alterations of a somatic cell Basic Properties of Cancer Cells 1. Loss of growth control Grow without growth signals Ignore inhibitory signals With telomerase Constant supply of telomerase Tumor can be benign or malignant ○ If benign, there is 50-50 chance that it can become malignant ○ Uncontrolled growth of cells Telomerase Adds new repeat units to the 3’ end of the telomere Enzyme at the end of telomere to restore DNA ends Enzyme needed when there is shortening of telomere when one is stressing out Centromere and Telomere Centromere ○ Central element of kinetochore The kinetochore is where DNA and proteins to which the spindle fibers attach Telomere ○ For stability of the chromosome tips Eppel’s Lab ○ Combines psychiatry with genetics ○ Found that academic distress contributes lesser degree in shortening centromere compared to psycho emotional stress such as childhood trauma Werner’s Syndrome Inherited disease Rapid aging Due to abnormal telomere maintenance 2. Seemingly Immortal Divide indefinitely No cell aging process due to constant supply of telomerase 3. Spread within the body Metastasis ○ Typically in stage 4 ○ In stage 3, the cancer cells are advanced but are still only in the organ of origin Enter the lymphatic system or vascular system ○ Conduit of cancer cells Cause lethal tumors 4. Angiogenesis Formation of blood vessels 4. Causes of Cancer Percival Pott ○ 1775 ○ First to correlate between environmental agent (carcinogens) and cancer ○ More cancer of nasal cavity and scrotum in chimney sweepers due to soot exposure Alter the genome Carcinogens Soot Cigarette smoke UV light 10-400 nm Frequencies > violet Causes pyrimidine dimers Brings 2 Thymine closer Distorts the double helix Blocks transcription and DNA replication DNA tumor virus: Polyomavirus Icosahedral with DNA genome From mammals (murines) and birds (caged) Common childhood and young adult infections Merkel cell polyomavirus ○ A carcinogen to humans ○ Mutated strain DNA Tumor Virus: Simian virus 40 Discovered in rhesus macaque Found in both monkeys and humans Leads to cancer in humans under natural conditions Induces in lab animals: 1. Primary brain and bone cancers 2. Malignant mesothelioma - Mesothelioma are epithelial cells that line the visceral organs 3. Lymphomas 5. Genetics of Cancer: Tumorigenesis Uncontrolled proliferation of a single cell Progression of mutations Cells don’t comply to regulatory machinery Invasive cancer ○ Malignant Precancerous Cells Pap Smear ○ Tests for detecting precancerous cells in the epithelial lining of cervix Larger nuclei 2 Genes in Carcinogenesis 1. Tumor-suppressor genes To prevent cell division To promote apoptosis 2. Oncogenes Promote no growth control Prevent apoptosis Oncogenesis follows 6. Strategies of combating Cancer 1. Passive Immunotherapy Administers antibodies that bind to targeted proteins on tumor’s surface Example: Herceptin ○ Inhibits activation of a receptor (HER 2) for breast cancer 2. Active (adoptive) Immunotherapy Immune cells are removed Stimulated in vitro ○ Genetically modified ○ Or with antigen Proliferate in culture Reintroduce into patient Boosts the immune system of the patient Example: Provenge vaccine ○ To train an immune response against prostate cancer cells ○ Extends patient’s life by ~ 4 months ○ Little impact on cancer cell numbers 3. Inhibiting activity of cancer-promoting proteins to stop uncontrolled growth and metastases Gleevec ○ Drug that inhibits a kinase in chronic myelogenous leukemia (CML) Patients continue to take Gleevec to remain in remission ○ Remission means reduced signs and symptoms but cancer is still present 4. Inhibiting Angiogenesis Avastin ○ FDA-approved drug for anti-angiogenesis 5. Live a healthy lifestyle! Eat vegetables and fruits with antioxidants Say “no” to toxic people Regular physical exercise Prayer life