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BIOL450 - Cancer Biology > Exam 2 > Flashcards

Exam 2 Flashcards

1
Q

Why does metabolism reprogramming occur?

A

Cancer cells reprogram their metabolism in order to rapidly grow

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1
Q

Do cancer cells exhibit aerobic respiration (oxidative phosphorylation) or glycolytic processes or both?

A

Both; Glycolysis just makes more acetate even in the presence of O2 (aerobic glycolysis)

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2
Q

What is the Warburg effect?

A

Tumor cells take up excess glucose and convert to lactate via glycolysis regardless of O2 concentration

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3
Q

Epigenetic mechanisms of reprogramming

A

metabolites act as co-factors and substrates of chromatin-modifying enzymes

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4
Q

How do oncogenes cause reprogramming?

A

Oncogenes like Myc, HIF-1a, and p53 act as transcription factors for metabolism-associated genes

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5
Q

Advantages of metabolic reprogramming

A

More nucleotides and biosynthetic starting materials in a shorter time, allows for shortened cell cycle and faster replication

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6
Q

What precursor do cancer cells need for nucleotide synthesis?

A

Ribose-5-phosphate from the pentose phosphate pathway

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7
Q

What precursor do cancer cells need for phospholipid synthesis?

A

Glycerol-3-phosphate

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8
Q

What precursor do cancer cells need to synthesize serine and glycine?

A

3-phosphate-glycerate

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9
Q

How do tumor cells suppress T cells?

A

tumor cells release more lactic acid to the extracellular microenvironment via the Warburg effect, and the lowered pH suppresses T cell immune response

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10
Q

What causes metabolic reprogramming?

A

Oncogenic factors like aberrant TFs, and environmental factors like diet

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11
Q

Oncometabolites

A

metabolites that are overproduced due to mutations and play a role in carcinogenesis

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12
Q

Example of oncometabolite pathway

A

Mutant isocitrate dehydrogenase (IDH) converts isocitrate into 2-hydroxyglutarate (instead of alpha-ketoglutarate) which inhibits histone methylases and prolyl hydroxylase, which degrades HIF-1a

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13
Q

HIF-1a

A

increases Warburg effect and angiogenesis

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14
Q

What cancer does IDH mutation cause?

A

acute myeloid leukemia (AML) - cancer of blood and bone marrow

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15
Q

What is a treatment for AML?

A

Enaisidenib is an oral allosteric inhibitor of IDH2 (Brand names Agios and Celgene)

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16
Q

What are the causative factors of diet?

A

Carcinogenic contaminants, dietary deficiencies, obesity, chronic alcohol consumption

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17
Q

What are the preventative factors of diet?

A

Antioxidants/ROS scavengers, nutrigenomics

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18
Q

Nutrigenomics

A

Dietary constituents can affect the expression of genes

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19
Q

Why is eating healthier better than taking supplements?

A

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.)

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20
Q

How does folate deficiency contribute to cancer?

A

reduction in folate derivatives results in DNA synthesis inhibition/DNA instability (mutations) and genomic hypomethylation

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21
Q

How does methotrexate work?

A

methotrexate competes with dihydrofolate, and inhibits dihydrofolate reductase, which in turn inhibits DNA synthesis; this is the opposite of what folate does

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22
Q

How is asparagine manipulated to treat acute lymphoblastic leukemia (ALL)?

A

ALL cells have a poor ability to synthesize asparagine, so treatment with asparaginase depletes asparagine levels

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23
Q

What are totipotent cells?

A

Stem cells that can give rise to all cell types plus extraembryonic cell types; only found in first few divisions after fertilization

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24
Q

What are pluripotent cells?

A

Stem cells that can give rise to any body cell type

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25
Q

What are transit-amplifying cells?

A

undifferentiated cells transitioning to differentiation

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26
Q

How are stem cells protected?

A

location, slow proliferation, apoptosis, Mdr1, conserved strand

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27
Q

Stem cells location

A

stem cells are usually located somewhere that is hard to get to; carcinogens have limited access

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28
Q

How fast do stem cells proliferate?

A

stem cells usually do not proliferate actively; when they do, it’s slow

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29
Q

What is Mdr1?

A

Multi-drug resistance 1 - protein in stem cells that can pump out most chemicals

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30
Q

Conserved strand hypothesis

A

Template strand is conserved through stem cells; daughter that receives non-template strand becomes transit-amplifying

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31
Q

Cancer stem cells (CSCs)

A

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

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32
Q

What proportion of tumor cells are CSCs?

A

a small subfraction; 1 in 1,000,000 in AML

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33
Q

What is the classical model of stem cell division?

A

Division is intrinsic and assymetrical; gives rise to one daughter cell and one lineage-committed daughter cell

34
Q

What is the neutral competition model of stem cell division?

A

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

35
Q

Why are stem cell mutations more deleterious than in other cells?

A

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

36
Q

How is the wnt pathway associated with colorectal cancers?

A

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

37
Q

How does cell growth occur in the intestines?

A

stem cells give rise to progenitor cells in crypts, cells move outwards over time, and cells outside of the crypts are differentiated

38
Q

How is the Hh pathway associated with cancer?

A

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

39
Q

What are the genes Hh promotes?

A

Cyclin D - cell cycle progression, Bcl2 - anti-apoptosis, VEGF - angiogenesis, SNAIL - metastasis

40
Q

In which hemopoietic lineages do disruptions occur in AML?

A

Granulocyte or Monocyte lineages

41
Q

What are some inhibitors of the Wnt pathway?

A

LKG974 - targets PORCN which modifies WNT, Ipafricet - binds WNT, Vantictumab - binds Frizzled, PRI-724 - interrupts interaction between beta-catenin and CBF

42
Q

What are some inhibitors of the Hh pathway?

A

Vismodegib, sonidegib, and glasdegib - target Smoothened, 5E1 and robotnikin - interact with Hh and prevent binding, GANT61 - blocks GLI binding to DNA

43
Q

What are some inhibitors of PcG proteins?

A

PTC-209 inhibits BMI1

44
Q

What are some Leukemia and differentiation therapies

A

All-trans retinoic acid (ATRA) led to hematological remission

45
Q

What do Polycomb Group proteins (PcG proteins) do?

A

Repress tumor suppressors in stem cells; release genes after differentiation; in cancer, allow self-renewal and ubiquitination (mark for degradation) of p53

46
Q

What are the checkpoints in the cell cycle?

A

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

47
Q

What is a bistable switch?

A

When stimulus is present, activator is dominant; when no stimulus, inhibitor is dominant

48
Q

What is immunopurification?

A

Specific anitbodies can be introduced to a protein mixture to isolate proteins that interact with them

49
Q

What do CDKs do?

A

CDKs are activated by cyclins and moderate the cell cycle

50
Q

Order of cyclins and CDKs

A

DEAB, 4221

51
Q

What are the mechanisms of CDK regulation?

A

association with cyclins, association with proteins that inhibit CDK activity, addition of phosphate groups that activate, and addition of phosphate groups that inactivate

52
Q

Timeline of the restriction checkpoint

A
  1. No GFs, Rb inhibits E2F
  2. GFs cause Cyclin D levels to increase
  3. Cyclin D and CDK 4/6 phosphorylate Rb
  4. E2F is no longer inhibited, Cyclin E is expressed
  5. Cyclin E and CDK 2 fuels positive feedback on P-Rb and E2F
  6. G1 -> S
53
Q

What proteins are associated with Rb?

A

HDAC, E2F, and DP

54
Q

What happens when Rb is initially phosphorylated?

A

HDAC is released, Cyclin E genes are moderately expressed

55
Q

What initially phosphorylates Rb?

A

Cyclin D and CDK 4

56
Q

What happens when Rb is phosphorylated a second time?

A

Rb releases from E2F and DP; cyclin E genes are fully expressed

57
Q

What phosphorylates Rb second?

A

Cyclin E and CDK 2

58
Q

What viral proteins bind Rb and when?

A

E7 (HPV), Tag (SV40), E1A (Adenovirus); only bind to hypophosphorylated form

59
Q

What does HDAC do?

A

Removes acetyl groups from histones and decreases transcription

60
Q

How are cyclin mutations and cancer related?

A

High activation of cyclins can result in cell dividing when it’s not supposed to = cancer w/ poor prognosis

61
Q

how do CDK inhibitors work?

A

Bind to CDK and inhibit checkpoint activation

62
Q

What cell cycle targets for therapy are there?

A

Inhibition of checkpoint kinases (Chk1 and Chk2), inhibition of mitotic spindle

63
Q

Which caspase (s) are associated with the extrinsic apoptosis pathway?

A

caspase 8

64
Q

Which caspase is associated with the intrinsic apoptosis pathway?

A

caspase 9

65
Q

What crosstalk is there between intrinsic and extrinsic pathway?

A

Caspase 8 cleaves Bid and Bid translocates to mitochondria; mitochondria outer membrane permeability increases and apoptosis occurs

66
Q

How does p53 activate apoptosis?

A

p53 activates transcription of PUMA, which competes with p53 for binding with BCL-x; free p53 activates BAX, which induces apoptosis

67
Q

How does BCL2 inhibit apoptosis?

A

BCL2 binds pro-apoptotic proteins (Cyt-C, Apaf-1, and Procaspase 9) and prevent formation of the apoptosome

68
Q

How does XIAP inhibit apoptosis?

A

XIAP binds and inhibits caspase 3 and caspase 7

69
Q

How do cancer cells manipulate caspase activity?

A

cancer cells use IAPs to inhibit active caspases

70
Q

What are three alternative death pathways?

A

Necroptosis, Autophagy, Mitotic Catastrophe

71
Q

Why do cells use autophagy

A

Beclin-1 induces autophagy to prevent necrosis

72
Q

What is TRAIL

A

TNF-related apoptosis-inducing ligand; stimulates apoptosis with or without p53; found in many cancer cells

73
Q

Apoptotic therapies

A

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

74
Q

Why does chemotherapy not work for some cancers?

A

Chemotherapy induces apoptosis, so it requires an intact pathway

75
Q

How does cancer avoid apoptosis?

A

Mutation, epigenetic downregulation of caspases, chromosomal translocations, altered levels of miRNA, induction of IAP gene expression

76
Q

Are oncogenes inherited?

A

No, only proto-oncogenes

77
Q

Are tumor-suppressor genes inherited?

A

They can be

78
Q

Are de novo mutations in germ cells more likely to occur during oogenesis or spermatogenesis?

A

Spermatogenesis; more divisions

79
Q

What are the mechanisms for LOH?

A

Nondisjunction, Nondisjunction and Duplication, Mitotic Recombination, Gene Conversion, Deletion, Point Mutation

80
Q

Is LOH necessary for p53-related cancers?

A

No; WT/Mutant p53 give dominant negative phenotype

81
Q

Upstream activators of p53

A

DNA damage, Oncogene activation, Cell stress

82
Q

Downstream actions of p53

A

Cell cycle halt, apoptosis, dna repair, angiogenesis inhibition

83
Q
A

BIOL450 - Cancer Biology (2 decks)

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