Lecture 17 Slides
rh
CANCER,
AGEING
and
METABOLISM
difficulties in being a long-lived MCO
cancer
ageing
difficulties in being a long-lived MCO
quantity
quality
cancer
pathogens:
differences
are clearer
cancer cells:
differences
are subtle
what are other adaptive features of
tumor cells?
how are they different
from normal cells?
cell biology
genomics
proteomics
metabolism
fast-growing cells in midst of stationary cells
F
remove
front layer
F
fast-growing cells in midst of stationary cells
starved for oxygen
lack of nutrients
low O2 causes transcriptional response
hypoxia-inducible factor: HIF1-a
fast-growing cells in midst of stationary cells
low oxygen
HIF1-a
increased
glycolysis
angiogenic
factors
“The prime cause of cancer is the
replacement of the respiration of oxygen
... in normal body cells by fermentation
of sugar”
Otto Warburg 1956
Warburg ca 1950s…
“The prime cause of cancer is the
replacement of the respiration of oxygen
... in normal body cells by fermentation
of sugar”
Otto Warburg 1956
Craig Thompson, M.D.
President, Memorial Sloan-Kettering
Science, May 2009
Warburg ca 2010…
“The prime cause of cancer is the
replacement of the respiration of oxygen
... in normal body cells by fermentation
of sugar”
Otto Warburg 1956
Tumor cells derive nearly all of their fatty
acids from de novo synthesis
Sidney Weinhouse 1953
what are the special features
of tumor cell metabolism?
Craig Thompson, M.D.
President, Memorial Sloan-Kettering
is glucose-dependent FA synthesis
an “achilles heel” of tumor cells?
remember citrate lyase?
fig 21-10
citrate lyase as an anabolic carbon source…
fig 21-10
FA synthesis in glycolytic tumor cells
Hatzivassiliou et al. (2005)
Cancer Cell 8, 1-11
pre-developed drugs...
citrate
citrate
lyase
AcCoA
statins
cholesterol
fatty acids
Both AcCoA availability and NAD+ regeneration are blocked by
inhibiting citrate lyase
fig 21-10
citrate lyase inhibitors
Do citrate lyase inhibitors block tumor
cell growth?
Do citrate lyase inhibitors block tumor
cell growth?
A new metabolic pathway in cancer?
A new metabolic pathway in cancer?
~ 80% of gliomas have a mutation in IDH1
cytoplasmic version of IDH, uses NADP+
mutation is always in R132, mostly R132H
always heterozygous… why?
A new metabolic pathway in cancer?
A new metabolic pathway in cancer?
metabolic profiling (metabolomics) revealed
an abundance of 2-hydroxyglutarate… ???
could this be a product of the mutant IDH?
A new metabolic pathway in cancer?
mutant
A new metabolic pathway in cancer!
How does production of 2OH-glutarate
benefit the glioma cancer cell?
programmed cell death: apoptosis
a dedicated signaling pathway for killing cells
in MCOs
apoptotic death has clear characteristics
employed in development and in both intraand inter cellular surveillance
main player...
The mitochondrion!
one way that apoptosis
is activated is by the
regulated release of
cytochrome c!
The mitochondrion!
one way that apoptosis
is activated is by the
regulated release of
cytochrome c!
difficulties in being a long-lived MCO
quantity
quality
difficulties in being a long-lived MCO
cancer
aging
difficulties in being a long-lived MCO
in adult organisms (like us)
many cells must live for the
entire lifetime without
replacement
all organisms have finite lifespans
old and young yeast
old and young C. elegans
1 day old
13 days old
old and young people
The Search for The Fountain of Youth
Ponce de Leon
the only known mammalian longevity enhancer...
the only known mammalian longevity enhancer...
caloric restriction (CR)
30-40% balanced decrease
30% or more increase in longevity
yeast, rotifers, flies, worms, fish,
spiders mice, rats, birds
how about in CR in humans or primates?
Okinawan centenarians analysis
how about in CR in humans or primates?
Okinawan centenarians analysis
One controlled human study
how about in CR in humans or primates?
Okinawan centenarians analysis
One controlled human study
Biosphere 2
Biosphere 2
how about in CR in humans or primates?
Okinawan centenarians analysis
One controlled human study
Biosphere II
NIH rhesus monkey study
how does CR make things live longer?
oxidative stress hypothesis
respiratory leak of electrons to oxygen
O2
O2
produces damage-causing ROS
ROS: reactive oxygen species
highly reactive molecules produced from
capture of electrons by O2
O2
+
e-
O2 -
˙
superoxide
anion
others:
H2O2
˙
HO
˙
(NO )
ROS: reactive oxygen species
highly reactive molecules produced from
capture of electrons by O2
cause damage to
DNA
protein
possible amplification loop
mito
ROS
lipids
Possible effects of CR on ROS levels
Decreased production of ROS
altered rate of e flow
metabolic adaptations of mitos
Increased removal of ROS
how does CR make things live longer?
correlated with decreased insulin levels and
increased insulin sensitivity
possible effects of insulin signaling on
longevity-associated processes?
BUT: many other relevant effects of CR!!
are there master “aging” genes?
it is easy to imagine that organisms
have multiple systems that are each
required for maintained life
meaning
that the genes that determine each
system’s function could each be “aging”
genes
nevertheless...
progeria: an accelerated aging syndrome
13 year old
John Tacket
Francis Collins
of HGP and NIH
progeria: an accelerated aging syndrome
search for genes involved in aging
S. cerevisiae
C. elegans
aging mutants in C. elegans
13 day old
wild-type
13 day old
mutant
aging mutants in C. elegans
what genes emerged
from this study?
DAF2 insulin receptor homologue!
1
wild type
daf-2
.5
0
0
20
40
Days
60
80
aging mutants in C. elegans
what genes emerged
from this study?
DAF2 insulin receptor homologue!
recall that insulin signals increased
abundance: the opposite of CR
aging mutants in C. elegans
what genes emerged
from this study?
Complex I-V respiratory chain!
consistent with the idea that mitochondrial
activity contributes to aging
aging mutants in C. elegans
what genes emerged
from this study?
EAT gens control food intake
a genetic version of CR!
A model
of CR
(in worms)
Food
insulin
signal
nutrient
metabolism
ETC activity
AGING
A genetic
test of this
idea
In fact, all three aging pathways appear
separate (in worms)
daf2
(insulin)
Food
mito
activity
AGING
AGING
AGING
Is this true in mammals?
How about positive acting
genes in longevity?
gene
gene
AGEING
AGEING
ageing mutants in yeast
extra
copies
of UTH4
two
different
mutants
w.t.
a longevity gene in yeast
SIR2
a novel enzyme:
NAD+ dependent protein deacetylase
NH-Ac
NH2
SIR2
protein
NAD+
protein
SIR2 is broadly involved in longevity
increasing SIR2 activity
increases lifespan in
yeast
C. elegans
Drosophila
mammalian cells (??)
IS Sir2 broadly involved in longevity?
A molecular fountain of youth?
the search is on for STACs: Sir Two
Activating Compounds
resveratrol: a natural
activator of SIR2...
increases lifespan in yeast, flies, C.elegans
or does it?
Resveratrol
imitates the
genetic
effects of
caloric
restriction