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HemOnc Week 3 > LM 8.2: Cancer Cell Signaling > Flashcards

LM 8.2: Cancer Cell Signaling Flashcards

1
Q

what is apoptosis?

A

cell-suicidal program that proceed according to a precisely co-ordinated schedule

it’s a normal physiological program cells employ to eliminate various cell types as part of the normal developmental program of all metazoan

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2
Q

what happens to the cell during apoptosis?

A
  • membrane blebbing
  • nucleus condensation
  • fragmentation of chromosomal DNA
  • pyknosis = a process that accompanies apoptosis and involves condensation of chromatin and collapse of nuclear structure

the apoptotic cells will be ingested by itinerant macrophages

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3
Q

what is staurosporine?

A

an apoptosis-inducing drug

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4
Q

which organelle is involved in apoptosis?

A

mitochondria

mitochondria regulate apoptosis through cytochrome C release!!

cytochrome C is stored in the space between the outermost mitochondrial membrane and the inner membranes, where it normally plays a key role in ETC

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5
Q

what causes the release of cytochrome C from mitochondria?

A

Bcl-2-related proteins lead to the release of cytochrome C from the mitochondria into the cytoplasm

initially, the distribution of cytochrome C coincides with the distribution of mitochondria in the cytoplasm

but as apoptosis proceeds, cytochrome C increases in the cytoplasm and there’s also evidence of nucleus fragmentation

you can see this all in a FISH

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6
Q

what domains does the Bax protein family have?

A

BH3, BH1, BH2 and transmembrane domains

they have many domains that are homologous to domains of Bcl-2

members of the Bax family normally are inactive form in the outer mitochondrial membrane OR in the cytosol

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7
Q

what are the domains of the Bcl-2 protein family?

A

BH1, BH2, BH3, BH4 and transmembrane domains

BH4 domain functions to inhibit apoptosis by blocking release of calcium ions from the endoplasmic reticulum

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8
Q

what do the Bax proteins and Bcl-2 proteins do?

A

they are both pro-apoptotic proteins

both classes of proteins are activated and/or translocated to the mitochondria by pro-apoptotic signals

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9
Q

what is the BH3-only family of proteins?

A

BH3

inactive members of the BH3-only family reside in the cytosol

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10
Q

what is the apoptotic caspase cascade?

A
  1. pro-apoptotic signals open channels in the outer mitochondria membrane and release cytochrome C and Smac/DIABLO
  2. cytochrome C aggregate with Apaf-1 to form an apoptosome (7-spoked wheel)
  3. the apoptosome attracts and converts procaspase 9 into active caspase 9
  4. active caspase 9 cleaves and activates procaspases 3,6 and 7 which converts them into executioner caspases
  5. active caspase 3,6 and 7 cleave various “death substrates” whose products create the apoptotic cell phenotype
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11
Q

what are some death substrates?

A

ICAD

vimentin

actin

lamin

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12
Q

what are IAPs?

A

inhibitors of apoptosis

they attach to and inactivate caspases so that they can’r cleave death substrates that will lead to the apoptotic cell phenotype

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13
Q

what does SMAC/DIABLO do?

A

pro-apoptotic signals open channels in the outer mitochondria membrane and release cytochrome C and Smac/DIABLO

Smac/DIABLO antagonize inhibitors of apoptosis (IAPs) which protects the caspases from IAP inhibition

SMAC facilitates apoptosis by blocking the caspase inhibitor X-linked inhibitor fo apoptosis proteins (XIAP)

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14
Q

what are the steps of the extrinsic apoptotic pathway?

A
  1. death receptors like TRAILR or FAS bind to their ligands (like tumor necrosis factor (TNF)- related apoptosis inducing ligand (TRAIL)
  2. the ligand binding can activate initiator caspases 8 & 10 through dimerization mediated by adaptor proteins like FAS-associated death domain protein (FADD)
  3. active caspase-8 and caspase-10 then cleave and activate the effector caspase-3 and caspase-7 which leads to apoptosis
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15
Q

what are the steps of the intrinsic apoptotic pathway?

A

aka the mitochondrial pathway of apoptosis that’s triggered by cell stressors like DNA damage, ER stress, hypoxia and metabolic stress

  1. cell stressors engage BCL-2 homology domain 3 (BH3)-only protein activation
  2. active BH3 activates BAX and CAK which triggers MOMP (BCL-2 proteins inhibit both BH3-only proteins and activated BAX & BAK)
  3. mitochondrial inter membrane space proteins like second mitochondria-derived activator of caspases (SMAC) and cytochrome C are released into the cytosol
  4. cytochrome C interacts with apoptotic protease activating factor 1 (APAF1) which triggers apoptosome assembly
  5. apoptosome assembly activates caspase 9
  6. active caspase-9 activates caspase 3 and 7 leading to apoptosis
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16
Q

what do BCL-2 proteins inhibit?

A

BCL-2 family proteins are anti-apoptotic proteins!

BCL-2 proteins inhibit both BH3-only proteins and activated BAX & BAK in the intrinsic apoptotic pathway

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17
Q

what enables crosstalk between the extrinsic and intrinsic apoptotic pathways?

A

caspase 8 from the extrinsic pathway will cleave the BH3-only protein BH3-interacting death domain agonist (BID)

the cleavage of BID enables crosstalk between the extrinsic and intrinsic apoptotic pathways because it activates BAX and BAK in the intrinsic pathway

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18
Q

how do cancer cells change the apoptotic pathway?

A

in various cancer cell types, the levels or activity of important pro-apoptotic proteins are decreased while the levels/activity of certain anti-apoptotic proteins may be increased

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19
Q

how does p53 activate the apoptotic pathway?

A
  1. it induces expression of the gene encoding the FAS death receptor so that it’s displayed at the cell surface – this sensitizes the cell to any FAS ligand that may be present in the extracellular space
  2. induces expression of IGF-binding protein-3 so that it’s released into the extracellular space where it binds and sequesters IGF-1 and IGF-2 which are the pro-survival, anti-apoptotic ligand of the IGF-1 receptor

in the absence of IGFBP-3, IGF1 would bind to its receptor and cause release via P13 kinase of anti-apoptotic signals in the cell, including those leading to the inactivation of the pro-apoptotic preotins

  1. drives expression of the FOXO3 pro-apoptotic transcription factor as well as Bax, the pro-apoptotic BLC-2 related protein
  2. inactivates anti-apoptotic agents
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20
Q

what are some of the pro-apoptotic proteins?

A

Bad (related to BCL-2)

FOXO3

IKB

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21
Q

what is Bax?

A

a pro-apoptotic BCL-2 related protein

causes the release of cytochrome C and other proteins form the mitochondria

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22
Q

what are the two mechanisms that regulate the replicative capacity of cells?

A
  1. measure the cumulative physiologic stress: cells stop proliferating once that damage exceeds a certain threshold causing cells to enter into senescence
  2. count how many replicative generations a cell linage has pass through and triggers apoptosis once the allowed quota has been reached and enter into a state termed crisis

replicative senescence and crisis are two hurdles cells need to overcome in order to proliferate indefinitely aka cancer

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23
Q

what’s the general pathway of how you bypass senescence?

A

senescence = the condition or process of deterioration with age; no more proliferation

you can bypass it with the expression of a tumor oncogene

expression of oncogenes will extend replicative capacity with another 10-20 generation before hitting crisis resulting in wide spread apoptosis in most cells in the population

once cells enter senescence they stop proliferating but remain viable

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24
Q

what does a cell in senescence look like?

A

it stops proliferating but remains viable

they develop extremely large cytoplasms giving them a fried egg appearance

they also express acidic B-galactosidase enzyme which can be detected by supplying them with a substrate that turns blue upon cleavage by this enzyme

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25
Q

how does the amount of oxygen effect the proliferation capacity of cells?

A

they proliferate way more at 3% oxygen than 20% oxygen because 3% oxygen concentration is what the body’s oxygen level is

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26
Q

what’s the DNA sequence of a telomere?

A

5’- TTAGGG-3’ repeats thousands of times

these repeat sequences + proteins make a telomere!

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27
Q

what is a 3’ overhang of a telomere?

A

telomere DNA has a 3’ overhang end because of the DNA end replication problem

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28
Q

what is the G-rich strand of a telomere?

A

G-rich strand of telomeric DNA extends beyond the C-rich strand

this is what creates the 3’ overhang that is often several hundred nucleotides long BUT this overhang is still way shorter than the double stranded portion of telomeric DNA

the double stranded part is made up of the G-rich strand and the C-rich strand

29
Q

what is the function of a telomere?

A

prevents the end-to-end fusion of chromosomal DNA molecules and hence, the fusion of chromosomes with one another

telomeric DNA is protected from degradation by a group of proteins associated to the telomere called the shelterin complex

30
Q

what is the shelterin complex?

A

a group of proteins associated to the telomere that protect it

TRF1 and TRF2 bind to the double stranded DNA portion of the telomere

POT1 binds to the single stranded 3’ overhang of a telomere

TIN2 and TPP1 connect TRF1 and TRF2 to POT1

31
Q

how can a telomere tell you about cell proliferation?

A

a telomere is a counting device that counts the total # of growth and division cycles each cell goes through since its founding in the early embryo

you can tell how long a telomeric restriction fragment (TRF) is via gel electrophoresis followed by Southern blotting analysis with a probe that recognizes the TTAGGG sequence

TRFs grow shorter with every successive passaging by 50-100 base pairs per cell generation - they erode each cycle to the point that they can’t protect the ends of chromosomal DNA

when the TRFs got to a certain shortness, they enter crisis – later, the cells would emerge spontaneously from crisis and become immortalized where they would maintain their telomeric DNA at slightly longer sizes than those seen in crisis

32
Q

how to cells emerge from crisis?

A

by regenerating their telomeres through the actions of the telomerase enzyme which functions specifically to elongate telomeric DNA

33
Q

what mechanisms do cancer cells use to bypass senescence?

A

they inactivate two major tumor suppressor pathways: p53 and p16/RB

  1. p53 mediates cell-cycle arrest through p21 in response to physiologic stresses – p21 inhibits all G1/S and M phase CDK enzymes

p53 is often inactivated or lost in cancer

  1. p16 blocks the G1 CDK enzyme = CDK4/CDK6 cyclin D complex

without p16, there would be uncontrolled G1/S transitions

34
Q

what does telomerase do?

A

elongates telomeric DNA so that the cell can exit crisis

ex. a population of human embryonic kidney cells was destined to enter crisis by 40 days but when hTERT, a telomerase enzyme, was ectopically expressed in these cells they gained the ability to proliferate indefinitely

35
Q

how does p53 prevent senescence?

A

p53 mediates cell-cycle arrest through p21 in response to physiologic stresses – p21 inhibits all G1/S and M phase CDK enzymes

p53 is often inactivated or lost in cancer

36
Q

how does p16/RB prevent senescence?

A

p16 blocks the G1 CDK enzyme = CDK4/CDK6 cyclin D complex

normally CDK4/6-cyclin D complex increases the phosphorylation state of RB which causes it to release the transcription factor E2F

E2F mediates the transcription of several cellular genes that are involved in the G1–>S progression like ribonucleotide reductase, dehydrofolate reductase, thymidine kinase, thymidylate synthase, CDC2, cyclin A and cyclin E

some of these enzymes increase production of deoxynucleoside triphosphates (dNTPs) which are needed for the G1 –> S transition

without p16, there would be uncontrolled G1/S

37
Q

which polymerases are involved in DNA replication?

A

polymerase α, δ and ε

38
Q

what are the roles of the different polymerases in DNA application?

A

polymerase δ is responsible for the bulk of lagging strand synthesis

polymerase ε carries out leading strand synthesis and proofreading

39
Q

what are some DNA replication errors?

A

polymerase δ in lagging strand synthesis will occasionally stutter aka skip a base when copying repeating sequences of DNA like a microsatellite sequence

so the newly synthesized strand may acquire an extra base or may lack a base

40
Q

what is spontaneous depurination?

A

it effects guanine within DNA and leaves behind a deoxyribose

purines = guanine and adenine

it’s a DNA replication error

41
Q

how does deamination cause DNA errors?

A

effects purine and pyrimidine bases

leads to changes in nucleotide sequence unless the are repaired

deamination of 5-methylcytosine yields thymine but since that base is naturally present in DNA, it’s not always recognized as being a mistake by repair machinery – this explains the frequent mutations at sites with this methylated base

42
Q

how does oxidation of DNA bases cause DNA errors?

A

ROS often oxidize DNA bases and if the oxidation isn’t fixed then it causes mutations

two common oxidation reactions involve

  1. deoxyguanosine (dG) which is oxidized to 8-oxo-deoxyguanosine

8-oxo-dG can mispair with deoxyadenosine instead of forming a normal base pair with deoxycytosine – if 8-oxo-dG isn’t removed then an A instead of C get put into the DNA

  1. deoxy-5-methylcytosine (d5mC) nucleotide that is present in methylated CpG sequences

upon oxidation d5mC forms an unstable base that rapidly deaminates to form deoxythymidine glycol (dTg)

43
Q

how does UV radiation damage DNA?

A

UV radiation produces covalent cross-links between adjacent pyrimidine bases in DNA

these structure are relatively stable chemically and must be removed

44
Q

how can PAHs damage DNA?

A

BP is a common PAH (polycyclic aromatic hydrocarbons)

when BP undergoes two successive oxidation reactions mediated by cytochrome P450 it’s converted to BPDE

BPDE is the ultimate carcinogen because it’s able to directly attack and form covalent adducts with DNA bases which can then generate oncogenic mutations

45
Q

how can exogenous alkylating agents damage DNA?

A

they add alkyl groups to DNA bases like a methyl group

these methyl groups can also be generated endogenously by the inadvertent actions of S-adenosyl methionine

46
Q

how does the body protect DNA from UV damage?

A

melanosomes-vesicles carrying melanin pigment that have been transferred from melanocytes into keratinocytes in the basal layers of the epidermis

once the melanosomes are acquired by the keratinocytes they are assembled into tiny sun umbrellas that sit above keratinocyte nuclei to shield them from UVB radiation

keratinocyte nuclei without umbrellas sustain 4x more UV-induced DNA damage

47
Q

what does GST do?

A

glutathione S-transferase

it detoxifies a number of reactive compounds before they’re able to react with cellular target molecules like DNA

the SH group of the glutathione is used to disrupt the highly reactive epoxide group of a compound that has suffered oxidation

a lot of prostate carcinomas show the loss of expression of an important GST

48
Q

what is mismatch repair used for?

A

used to detect nucleotides of normal structure that have been incorporated into the wrong positions during DNA replication

49
Q

what are the steps of mismatch repair?

A

MutSα and MutLα collaborate to initiate repair of mismatched DNA

MutSα scans the DNA and locates a mismatch then

MutLα scans the DNA for single strand nicks to identify the strand that was recently synthesized - undermethylation of the new strand will also help identify it

MutLα then triggers degradation of this strand back through the detected mismatch, allowing for repair DNA synthesis to follow

  1. binding of mismatch proofreading proteins
  2. DNA scanning detects nick in new DNA strand
  3. strand removal
  4. repair DNA synthesis
50
Q

what does MGMT do?

A

methylguanine-DNA methyltransferase is a dealkylating repair enzyme that repairs DNA!

O6-MGMT restores an altered guanosine to its normal structure by removing the alkyl group from the O6 atom of guanine

if this isn’t repaired, the alkylated guanosine often leads to a G-to-A transition mutation

lots of tumors have a methylated MGMT promoter which silences MGMT

51
Q

how does BER work?

A

BER = base excision repair

  1. DNA N-glycosylase enzyme recognizes chemically altered bases and cleaves the glycosyl bond linking the altered base and the deoxyribose
  2. the base-free deoxyribosylphosphate is then exited by APE enzyme that is specific for base-free sugars
  3. the resulting single nucleotide gap is filled by DNA polymerase B and sealed with DNA ligase

**usually repairs lesion in DNA that are from endogenous sources like ROS and depurination events

52
Q

how does NER work?

A

nucleotide excision repair

an enzyme recognizes bulky helix-distorting lesions and cleaves the oligotide sequence about 24 nucleotides on the 5’ side and 5 nucleotides on the 3’ side

the resulting 29 nucleotide strand gap in the DNA is then filled by DNA polymerase δ or ε which work together with PCNA (proliferating-cell nuclear antigen)

***mostly repairs lesions created by exogenous agents like UV photons and chemicals

53
Q

what’s the difference between what DNA repair NER vs. BER does

A
  1. NER largely repairs lesions created by exogenous agents like UV photons or chemicals

mostly repairs bulky, helix-distorting alterations and requires a large multi protein complex to do it

  1. BER usually repairs lesion in DNA that are from endogenous sources like ROS and depurination events

mostly repairs lesions that don’t create structural distortions of DNA double helix

54
Q

what is homology directed repair?

A

the repair of dsDNA breaks during the S phase and G2 phase that depends on the ability of the repair apparatus to consult the sequences in the undamaged sister chromatid that was formed, together with the damaged chromatin, during the most recent S phase

55
Q

what are the steps in HR repair?

A
  1. removal of one of the two DNA strands at each of the ends formed by a dsDNA break by an exonuclease
  2. each of the resulting ssDNA strands then invade the undamaged sister chromatid DNA that has been unwound by the repair apparatus
  3. ssDNA strands from the damaged chromatid are then elongated in a 5’-3’direction by a DNA polymerase using the strands of the sister chromatid’s DNA as templates
  4. the extended ssDNA strands are released from the sister chromatid and pair with one another allowing for further elongation by a DNA polymerase and ligase
56
Q

which enzymes are involved in HR repair?

A

RAD51

BRCA1

BRCA2

57
Q

what is nonhomolgous end joining?

A

NHEJ is used to restore a DNA double helix following a double strand break when the nucleotide sequences from a sister chromatid are not available to instruct the repair apparatus how these ends should be properly joined

the resection of single strands from both broken ends results in ssDNA overhands that can then be joined to one another

the reconstructed double helix lacks some of the base pairs that were present in the original undamaged DNA helix

58
Q

in what phase of the cell cycle does NHEJ mostly happen?

A

G1

this is because sister chromatids aren’t available to allow HR repair to happen

59
Q

what DNA repair system is messed up in patients with XP?

A

NER

60
Q

what are the constraints on targeting defective proteins in cancer cells for therapeutic intervention?

A

anticancer drugs usually inhibit rather than enhance biochemical functions so targeting tumor suppressor proteins doesn’t really work

activation of oncoprotein that initiate the multi-step tumor progression may not play critical roles later when the full-blown malignant phenotype has been finally acquired

the biochemistry of proteins also determines if they are attractive targets for intervention

61
Q

what enzyme is a difficult target for cancer drugs?

A

kinases

it’s hard to make specific kinase inhibitors because they all have really similar structures and really similar catalytic regions

so it’s hard to find inhibitors of one kinase receptor that won’t effect another

62
Q

what is Gleevec?

A

an anti-cancer drug developed to inhibit the tyrosine kinase activity of the Bcr-Abl fusion protein active in chronic myelogenous leukemia

63
Q

how are anti-cancer drugs developed?

A

the molecular structure of the target protein should inform the design of the chemical structures of the drugs that are being developed

you want the drug to be able to specifically bind to the catalytic cleft of the protein

64
Q

what do EGF-R antagonists do?

A

the two EGFR antagonists may be useful for treating a wide variety of tumor types (EGFR = epidermal growth factor receptor)

EGFR antagonists have an affinity for the ATP-binding site of the tyrosine kinase receptor

the two drugs are similar but not identical properties and act by blocking the ATP-binding site of the receptor-associated kinase

once cancer cells are deprived of receptor signaling through inhibition of the EGFR, they should lose the benefit of its strong mitogenic and anti-apoptotic signals

65
Q

what is multiple myeloma?

A

a malignancy of the B-cell linage in which a single clone of antibody-producing plasma cells dominates the bone marrow

the myeloma cells create osteolytic bone lesions that lead to fractures and they ultimately crowd out the remaining cellular components of the marrow resulting in severe immune depression and death from infection

death within 3-5 years after diagnosis

66
Q

what is Velcade used for?

A

it’s a proteasome inhibitor used to treat multiple myeloma

it decreases the amount of antibodies in the blood and improves the cellular contents of the marrow

when Velcade is used with Melphalan which is an alkylating chemo drug used to treat MM, melphalan was able to induce widespread apoptosis - on its own, melphalan wasn’t able to induce such widespread apoptosis

67
Q

how does Velcade work?

A

in normal and neoplastic cells, stress signals activate IKB kinase – IKK phosphorylates IKB, the inhibitor of NF-KB

this causes IKB to become ubiquitylated and degraded in proteasomes – NF-KB is then free to move into the nucleus where it activates the expression of numerous proliferation and anti-apoptotic genes

in the presence of Velcade, the ubiquitylated IKB can’t be degraded in the proteasomes because the latter have become engorged with unprocessed polypeptides

this leads to an accumulation of iKB in the cytoplasm and to the continued sequestration of NF-KN by the IKB molecules that have built up

as a consequence, NF-KB is prevented from moving into the nucleus and activating expression of anti-apoptotic genes

68
Q

what type of cancer is BRAF associated with?

A

BRAF kinase is mutated in half of cutaneous human melanomas

69
Q

what drug is used to treat BRAF mutations?

A

PLX4032 is used for the inhibition of oncogenic BRAF in metastatic melanoma

HemOnc Week 3 (22 decks)

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