The relationship between autophagy ＆ apoptosis

IMI CONFIDENTIAL

Gu Chunbo

2014.09.29

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Outline

1 Introduction of autophagy2 The interaction between autophagy and apoptosis3 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 cellsb) 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 pathwayc) 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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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.

2. The interaction between autophagy and apoptosis

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• 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.

2. The interaction between autophagy and apoptosis

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3. A latest research about autophagy and apoptosis

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Background

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• 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

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Figure 1. TMZ induces autophagy in LN-229 cells.

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ResultsFigure 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. TMZ-induced 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!