Exam 2 Flashcards
Why does metabolism reprogramming occur?
Cancer cells reprogram their metabolism in order to rapidly grow
Do cancer cells exhibit aerobic respiration (oxidative phosphorylation) or glycolytic processes or both?
Both; Glycolysis just makes more acetate even in the presence of O2 (aerobic glycolysis)
What is the Warburg effect?
Tumor cells take up excess glucose and convert to lactate via glycolysis regardless of O2 concentration
Epigenetic mechanisms of reprogramming
metabolites act as co-factors and substrates of chromatin-modifying enzymes
How do oncogenes cause reprogramming?
Oncogenes like Myc, HIF-1a, and p53 act as transcription factors for metabolism-associated genes
Advantages of metabolic reprogramming
More nucleotides and biosynthetic starting materials in a shorter time, allows for shortened cell cycle and faster replication
What precursor do cancer cells need for nucleotide synthesis?
Ribose-5-phosphate from the pentose phosphate pathway
What precursor do cancer cells need for phospholipid synthesis?
Glycerol-3-phosphate
What precursor do cancer cells need to synthesize serine and glycine?
3-phosphate-glycerate
How do tumor cells suppress T cells?
tumor cells release more lactic acid to the extracellular microenvironment via the Warburg effect, and the lowered pH suppresses T cell immune response
What causes metabolic reprogramming?
Oncogenic factors like aberrant TFs, and environmental factors like diet
Oncometabolites
metabolites that are overproduced due to mutations and play a role in carcinogenesis
Example of oncometabolite pathway
Mutant isocitrate dehydrogenase (IDH) converts isocitrate into 2-hydroxyglutarate (instead of alpha-ketoglutarate) which inhibits histone methylases and prolyl hydroxylase, which degrades HIF-1a
HIF-1a
increases Warburg effect and angiogenesis
What cancer does IDH mutation cause?
acute myeloid leukemia (AML) - cancer of blood and bone marrow
What is a treatment for AML?
Enaisidenib is an oral allosteric inhibitor of IDH2 (Brand names Agios and Celgene)
What are the causative factors of diet?
Carcinogenic contaminants, dietary deficiencies, obesity, chronic alcohol consumption
What are the preventative factors of diet?
Antioxidants/ROS scavengers, nutrigenomics
Nutrigenomics
Dietary constituents can affect the expression of genes
Why is eating healthier better than taking supplements?
Single-component supplements have been shown to increase cancer incidence in some cases, plus eating healthier allows you to reap the other benefits (antioxidants, less obesity, etc.)
How does folate deficiency contribute to cancer?
reduction in folate derivatives results in DNA synthesis inhibition/DNA instability (mutations) and genomic hypomethylation
How does methotrexate work?
methotrexate competes with dihydrofolate, and inhibits dihydrofolate reductase, which in turn inhibits DNA synthesis; this is the opposite of what folate does
How is asparagine manipulated to treat acute lymphoblastic leukemia (ALL)?
ALL cells have a poor ability to synthesize asparagine, so treatment with asparaginase depletes asparagine levels
What are totipotent cells?
Stem cells that can give rise to all cell types plus extraembryonic cell types; only found in first few divisions after fertilization
What are pluripotent cells?
Stem cells that can give rise to any body cell type
What are transit-amplifying cells?
undifferentiated cells transitioning to differentiation
How are stem cells protected?
location, slow proliferation, apoptosis, Mdr1, conserved strand
Stem cells location
stem cells are usually located somewhere that is hard to get to; carcinogens have limited access
How fast do stem cells proliferate?
stem cells usually do not proliferate actively; when they do, it’s slow
What is Mdr1?
Multi-drug resistance 1 - protein in stem cells that can pump out most chemicals
Conserved strand hypothesis
Template strand is conserved through stem cells; daughter that receives non-template strand becomes transit-amplifying
Cancer stem cells (CSCs)
subpopulation of tumor cells that can self-renew and give rise to phenotypically diverse cancer cells with limited proliferative potential that make up the rest of the tumor
What proportion of tumor cells are CSCs?
a small subfraction; 1 in 1,000,000 in AML
What is the classical model of stem cell division?
Division is intrinsic and assymetrical; gives rise to one daughter cell and one lineage-committed daughter cell
What is the neutral competition model of stem cell division?
Parental stem cells can give rise to two daughter stem cells, or one daughter stem cell and one differentiation-committed daughter cell, as determined by the space within the stem cell niche. Committed cells may show plasticity and may eventually re-enter the niche
Why are stem cell mutations more deleterious than in other cells?
If a stem cell mutates, the mutation is passed down to all subsequent stem cell generations and all types of differentiated cells arising from those stem cells
How is the wnt pathway associated with colorectal cancers?
90% of colorectal cancers result from changes to the Wnt pathway, but Wnt is rarely mutated. Usually APC is mutated or beta-catenin is activated
How does cell growth occur in the intestines?
stem cells give rise to progenitor cells in crypts, cells move outwards over time, and cells outside of the crypts are differentiated
How is the Hh pathway associated with cancer?
Gorlin syndrome: Mutant patched activates smoothened, genes are expressed; Basal cell carcinomas have altered Hh activity in hair follicle stem cells; Medulloblastomas have altered Hh signaling in neuron precursors; Inhibition of Hh inhibits growth in Gleevec-resistant cancers
What are the genes Hh promotes?
Cyclin D - cell cycle progression, Bcl2 - anti-apoptosis, VEGF - angiogenesis, SNAIL - metastasis
In which hemopoietic lineages do disruptions occur in AML?
Granulocyte or Monocyte lineages
What are some inhibitors of the Wnt pathway?
LKG974 - targets PORCN which modifies WNT, Ipafricet - binds WNT, Vantictumab - binds Frizzled, PRI-724 - interrupts interaction between beta-catenin and CBF
What are some inhibitors of the Hh pathway?
Vismodegib, sonidegib, and glasdegib - target Smoothened, 5E1 and robotnikin - interact with Hh and prevent binding, GANT61 - blocks GLI binding to DNA
What are some inhibitors of PcG proteins?
PTC-209 inhibits BMI1
What are some Leukemia and differentiation therapies
All-trans retinoic acid (ATRA) led to hematological remission
What do Polycomb Group proteins (PcG proteins) do?
Repress tumor suppressors in stem cells; release genes after differentiation; in cancer, allow self-renewal and ubiquitination (mark for degradation) of p53
What are the checkpoints in the cell cycle?
A restriction checkpoint that governs if the cell goes back into G0, DNA damage checkpoints before and during S (p53), DNA replication checkpoint at end of G2 (p53), and spindle checkpoint during M
What is a bistable switch?
When stimulus is present, activator is dominant; when no stimulus, inhibitor is dominant
What is immunopurification?
Specific anitbodies can be introduced to a protein mixture to isolate proteins that interact with them
What do CDKs do?
CDKs are activated by cyclins and moderate the cell cycle
Order of cyclins and CDKs
DEAB, 4221
What are the mechanisms of CDK regulation?
association with cyclins, association with proteins that inhibit CDK activity, addition of phosphate groups that activate, and addition of phosphate groups that inactivate
Timeline of the restriction checkpoint
- No GFs, Rb inhibits E2F
- GFs cause Cyclin D levels to increase
- Cyclin D and CDK 4/6 phosphorylate Rb
- E2F is no longer inhibited, Cyclin E is expressed
- Cyclin E and CDK 2 fuels positive feedback on P-Rb and E2F
- G1 -> S
What proteins are associated with Rb?
HDAC, E2F, and DP
What happens when Rb is initially phosphorylated?
HDAC is released, Cyclin E genes are moderately expressed
What initially phosphorylates Rb?
Cyclin D and CDK 4
What happens when Rb is phosphorylated a second time?
Rb releases from E2F and DP; cyclin E genes are fully expressed
What phosphorylates Rb second?
Cyclin E and CDK 2
What viral proteins bind Rb and when?
E7 (HPV), Tag (SV40), E1A (Adenovirus); only bind to hypophosphorylated form
What does HDAC do?
Removes acetyl groups from histones and decreases transcription
How are cyclin mutations and cancer related?
High activation of cyclins can result in cell dividing when it’s not supposed to = cancer w/ poor prognosis
how do CDK inhibitors work?
Bind to CDK and inhibit checkpoint activation
What cell cycle targets for therapy are there?
Inhibition of checkpoint kinases (Chk1 and Chk2), inhibition of mitotic spindle
Which caspase (s) are associated with the extrinsic apoptosis pathway?
caspase 8
Which caspase is associated with the intrinsic apoptosis pathway?
caspase 9
What crosstalk is there between intrinsic and extrinsic pathway?
Caspase 8 cleaves Bid and Bid translocates to mitochondria; mitochondria outer membrane permeability increases and apoptosis occurs
How does p53 activate apoptosis?
p53 activates transcription of PUMA, which competes with p53 for binding with BCL-x; free p53 activates BAX, which induces apoptosis
How does BCL2 inhibit apoptosis?
BCL2 binds pro-apoptotic proteins (Cyt-C, Apaf-1, and Procaspase 9) and prevent formation of the apoptosome
How does XIAP inhibit apoptosis?
XIAP binds and inhibits caspase 3 and caspase 7
How do cancer cells manipulate caspase activity?
cancer cells use IAPs to inhibit active caspases
What are three alternative death pathways?
Necroptosis, Autophagy, Mitotic Catastrophe
Why do cells use autophagy
Beclin-1 induces autophagy to prevent necrosis
What is TRAIL
TNF-related apoptosis-inducing ligand; stimulates apoptosis with or without p53; found in many cancer cells
Apoptotic therapies
Smac mimetics inhibit IAPs, GEM640 targets IAP mRNA, G-3139 targets Bcl-2 mRNA, BH3 mimetics bind and inhibit BCL-2, SAHA competes with HDAC and allow for transcription of Bid
Why does chemotherapy not work for some cancers?
Chemotherapy induces apoptosis, so it requires an intact pathway
How does cancer avoid apoptosis?
Mutation, epigenetic downregulation of caspases, chromosomal translocations, altered levels of miRNA, induction of IAP gene expression
Are oncogenes inherited?
No, only proto-oncogenes
Are tumor-suppressor genes inherited?
They can be
Are de novo mutations in germ cells more likely to occur during oogenesis or spermatogenesis?
Spermatogenesis; more divisions
What are the mechanisms for LOH?
Nondisjunction, Nondisjunction and Duplication, Mitotic Recombination, Gene Conversion, Deletion, Point Mutation
Is LOH necessary for p53-related cancers?
No; WT/Mutant p53 give dominant negative phenotype
Upstream activators of p53
DNA damage, Oncogene activation, Cell stress
Downstream actions of p53
Cell cycle halt, apoptosis, dna repair, angiogenesis inhibition
