Download 1 Introduction of autophagy

The relationship between autophagy ＆ apoptosis
Gu Chunbo
2014.09.29
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Outline
1 Introduction of autophagy
2 The interaction between autophagy and apoptosis
3 A latest research of interaction of autophagy and
apoptosis
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1 Introduction of autophagy
Definition: Autophagy, a cellular process of "self-eating" by which
intracellular components (organelles and macromolecules) are
degraded within the lysosome, is an evolutionarily conserved response
to various stresses.
Autophagy is associated with numerous patho-physiological
conditions, and dysregulation of autophagy contributes to the
pathogenesis of a variety of human diseases including cancer.
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1 Introduction of autophagy
The classification of autophagy: macroautophagy, microautophagy and
chaperone-mediated autophagy (CMA)
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1 Introduction of autophagy
Note:
1. Part of the cell itself is digested (self-eating) in autophagy in the presence of
inducing factors, but rare in the normal cells.
2. It is a rapid process: formation of autophagosome in 8 min, and complete
degradation in 2 h.
3. Autophagy is conservative in Eukarya and different types of cells including
cancer cells, which is beneficial to cell survival.
4. Dual actions of autophagy in the genesis and development of cancer.
a) in the different tumor cells
b) impacted by different external factors in the same type of cells.
c) enhanced autophagy in the early stage of tumor; weakened autophagy in
the development phase of tumor.
d) two-tier roles in the single tumor cell and the whole tumor.
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2. The interaction between autophagy and apoptosis
The relationship of autophagy and apoptosis is summarized below:
• Both can induce cell death.
a) they lead to cell death independently (no interaction)
b) autophagy is in the upstream of apoptosis pathway
c) autophagy is inhibited by apoptosis. When apoptosis is suppressed,
autophagy is induced to skill cells.
• Autophagy inhibits apoptosis by degrading impaired proteins and
DNA.
• Autophagy promotes apoptosis. Autophagy itself can not induce cell
death, but can provide energy for formation of apoptosome and
phagocytosis.
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2. The interaction between autophagy and apoptosis
Molecular mechanism for interaction of autophagy and apoptosis:
• Atg5: the dipolymer of Atg5 and Atg12 play a vital role in the
prolong of bilayer membrane of autophagosome; The products
degraded by calpain can act on Bcl-XL in mitochondria, inducing apoptosis
by activating Caspase.
• Bcl-2: It is well known that Bcl-2 is a protein that inhibits apoptosis. A recent
study found that Bcl-2 can inhibit the expression of Beclin-1 after coupling
with Beclin-1, resulting in weaken level of autophagy. Separating Bcl-2 from
Beclin-1 promotes autophagy and inhibits apoptosis.
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2. The interaction between autophagy and apoptosis
• p53: p53 is a common anti-oncogene, which exerts lethal effects
by enhancing apoptosis at transcription level. A study indicated
that p53 intensifies autophagy by acting on autophagy-related
gene. Another study showed that it is in cytoplasm but not cell
nucleus that p53 dampen-downs autophagy.
• DAPK (death-associated protein kinase): we know that the
combination of Beclin-1 and Bcl-2 attenuates autophagy.
However, activated DAPK can dissociate Bcl-2 from Beclin-1 by
phosphorylation at 119-Thr, enhancing autophagy. On the other
hand, DAPK up-regulates p53, leading to apoptosis.
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3. A latest research about autophagy and apoptosis
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Background
• Apoptosis, autophagy, necrosis and cellular senescence are key
responses of cells that were exposed to genotoxicants.
•Temozolomide (TMZ) is the first line chemotherapeutic drug ,
which induces several DNA adducts among which the minor
adduct O6-methylguanine (O6-MeG) is the mocytotoxic lesion, if
not repaired by O6-methylguanine-DNA methyltransferase
(MGMT) .
• The Types of DNA damage triggering these responses and their
interrelationship are largely unknown.
• Here the authors studied these responses in glioma cells treated
with the methylating agent temozolomide (TMZ)
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Results
Figure 1. TMZ induces autophagy in LN-229 cells.
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Results
Figure 2. TMZ-induced autophagy is MGMT dependent
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Figure 3. TMZ-induced autophagy is MMR and HR dependent.
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Figure 4. TMZinduced
autophagy
comes earlier
than apoptosis
and inhibits it.
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Figure 6. TMZ
induces
senescence in
LN-229 cells,
which is
dependent on
autophagy
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Thanks for your patience!
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