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Role of apoptosis in cancer progression
- 1. Why does cell proceed towards carcinogenesis when there are mechanisms to remove cells unfit for survival? Why does cell proceed towards carcinogenesis when there are mechanisms to remove cells unfit for survival? Monika Roll no: M-5626 Division of veterinary medicine Monika Roll no: M-5626 Division of veterinary medicine
- 3. • Process of actual formation of cancer which is characterised by progression of changes at the - Genetic - Epigenetic level - Ultimately lead to uncontrolled cell division • Multistep process Robinns basic pathology Carcinogenesis?Carcinogenesis?
- 7. MECHANISMS TO REMOVE CELL UNFIT FOR SURVIVAL MECHANISMS TO REMOVE CELL UNFIT FOR SURVIVAL
- 10. ApoptosisApoptosis • Apoptosis is a active energy dependent process that involves cleavage of DNA by endonucleases and proteins by proteases called CASPASES. Lowe et al., 2000
- 12. Necrosis • Local death of tissue within living tissue after degradative action of enzymes on the irreversible injured cell
- 13. • Potentially reversible process in which a cell that is stressed EATS itself. Elmore., 2007 • Characterized by the formation of cytoplasmic AUTOPHAGIC VESICLES • Targeted disruption of genes such as ATG5 that are involved in autophagy can inhibit cell death. • Autophagy has dual roles in cancer: - a tumor suppressor by preventing the accumulation of damaged proteins and organelles - as a mechanism of cell survival that can promote the growth of tumors Tait et al., 2014
- 14. Factors leading to defective autophagy: a)Beclin 1 mutation b) PI3K-Akt-mTOR pathway dysregulation Panda et al., 2015
- 15. What makes the cell to evade cell death and makes it cancerous? What makes the cell to evade cell death and makes it cancerous? Hanahan et al., 2011
- 18. Over expression of telomeraseOver expression of telomerase
- 19. Checkpoints in cell cycle the cell cycle is controlled by two classes of cell cycle proteins, cyclins and cyclin dependent kinases (CDKs), which physically associate to form a protein kinase that drives the cell cycle forward the cell cycle is controlled by two classes of cell cycle proteins, cyclins and cyclin dependent kinases (CDKs), which physically associate to form a protein kinase that drives the cell cycle forward most tumor cells lack the DNA damage-induced p53- dependent G1 checkpoint, increasing the likelihood that mutations will be propagated in these cells. most tumor cells lack the DNA damage-induced p53- dependent G1 checkpoint, increasing the likelihood that mutations will be propagated in these cells. Molecular Biology of Cancer
- 21. • Situated at the short arm of 17 chromosome • Mutated in most of the cancer cases • Repair of damaged DNA before S-phase in the cycle by arresting cell cycle in G1 phase untill the damage is repaired • Apoptic cell death if there is extensive DNA damage • p53 can lost its function: a) Non sense mutation or mis sense mutation b) Binding of normal p53 to viral oncoproteins p53p53 Molecular Biology of Cancer
- 24. High levels of FLICE FADD like IL-1 converting enzymeFADD like IL-1 converting enzyme Binds with DISC(death inducing signalling complex)Binds with DISC(death inducing signalling complex) Prevents activation of caspases 8Prevents activation of caspases 8 No apoptosis No apoptosis Elmore.,2007
- 25. Over expression of Bcl-2Over expression of Bcl-2
- 27. • Caretaker genes - Maintain the integrity of the genome by repairing DNA damage • Gatekeeper genes - Inhibit the proliferation or promote the death of cells with damaged DNA Categories of tumor suppressor genesCategories of tumor suppressor genes
- 29. RAS gene
- 30. • APC regulates the rates of proliferation and apoptosis • APC is important for cytoskeletal integrity, cellular adhesion, and Wnt signaling. • APC plays a role in the G1/S transition of the cell cycle by modulating expression levels of c-myc and cyclin D1 • full length APC is also important in maintaining intestinal cell migration up the crypt and inducing apoptosis APC(Adenomatous polyposis coli)APC(Adenomatous polyposis coli) Martinez et al.,2003
- 32. tumor suppressor gene ,role in induction of cell cycle arrest and apoptosis tumor suppressor gene ,role in induction of cell cycle arrest and apoptosis acts as a negative regulator of Akt activationacts as a negative regulator of Akt activation can induce apoptosis of mutated Or stressed cells to prevent tumor formation can induce apoptosis of mutated Or stressed cells to prevent tumor formation PTEN suppresses the PI-3K-mediated induction of blood vessel growth factors PTEN suppresses the PI-3K-mediated induction of blood vessel growth factors PTENPTEN Martinez et
- 33. Other factors.. family of Inhibition of Apoptosis Proteins - xIAP,BIRC2,BIRC3 Heat Shock Proteins - HSP27,HSP70 Casarett & Doull’s Toxicology 7th edition • deregulation in anoikis execution is emerging as a hallmark of cancer cells and contributes to the formation of metastasis in distant organs Paoli et al., 2013
- 34. Conclusion Oncogenic mutation distrupt apoptosis ,leading to tumor initiation,progression and metastasis Agents that induce apoptosis,autophagy can be used as anticancer drugs p53 mutation causes Li- Fraumenic syndrome Bcl-2 alteration causes hodgkin disease,breast cancer Bax deletion causes brain tumors