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Summary reader Molecular Regulation Of Health and Disease (HAP-31806)
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Reader Summary Molecular Regulation of Health and Disease1. MOLECULAR REGULATION OF ENERGY AND NUTRIENT METABOLISM
Difference cancer cells compared to normal cells:
Immortal
Display sufficiency in growth signals
Are invasive and have properties that support invasion and metastasis
o Have loss of contact inhibition
o Have reduced cellular adhesion
o Have loss of anchorage dependence
o Have less organized, more mobile surface proteins
o Show an altered secreted protein profile
Are resistant to programmed cell death
Have an altered nutrient and energy metabolism
o Show an increased rate of glycolysis
o Have a more negative surface charge of the cell membrane and sustained
angiogenesis
Cancer cells are re-programmed such that optimal growth
of the individual cell is facilitated, but at the expense of
the organism to which the cancer cell belongs
Hallmarks of cancer:
Sustaining proliferative signalling
Evading growth suppressors
Resisting cell death
Enabling replicative immortality
Inducing angiogenesis
Activating invasion and metastasis
Evading immune destruction
Reprogramming of energy metabolism
Cancer cell metabolism is programmed to optimize cell
growth, this means that a major goal of cancer cells is to produce the three major constituents of the
cell: protein, DNA and membranes. The major fuels that are consumed by cancer cells are glucose,
glutamine and fatty acids. ATP, NADH and NADPH are needed for all catabolic and anabolic processes
to proceed
Mitochondria:
organelles that reside in eukaryotic cells
have a double membrane (the mitochondrial outer membrane (MOM) and the mitochondrial
inner membrane (MIM))
Mitochondria have their own circular DNA
Mitochondrial DNA encodes for 13 proteins of the 1250 that are in it. The others are encoded
by nuclear DNA and imported into mitochondria via the so-called TOM (translocator of outer
membrane) and TIM (translocator of inner membrane) complexes
Functions:
o Produce ATP
o Respond to cellular energy requirements
o Regulate the balanced use of energy substrates in:
The urea cycle
, Calcium homeostasis
Amino acid metabolism
o Essential for heme and ironsulpur cluster biosynthesis
o Mediation of apoptosis and innate immune defence
o Oxidative signalling mediated by reactive oxygen species (ROS)
Mitochondria functions are substantially altered in cancer cells
Glycolysis:
Anaerobic
Provides 2 ATP per molecule glucose
High capacity/low efficiency system
End product can be 2 molecules of pyruvate, which are imported into mitochondria, or 2
molecules of lactate
o Pyruvate enters the TCA cycle
o TCA cycle breaks down acetyl CoA to generate CO 2 and reduce NAD+ to NADH and
FAD to FADH2
o Providing electrons to the electron transport complex (ETC)
The electrons are moved from complex to complex
Creating an electrochemical proton gradient
Resulting into ATP synthesis
Oxidative Phosphorylation (OXPHOS)
Generating 32-34 ATP per glucose
Reactive oxygen species (ROS):
The free radicals that are generated because of OXPHOS
Unpaired electrons
Interaction of unpaired electrons with O 2 results in the generation of superoxide ions (O 2-)
Potentially harmful
Enzymatic systems to inactivate ROS:
o Copper-Zinc Superoxide Dismutase
o Manganese Superoxide Dismutase
o Catalase (peroxisome) and glutathione peroxidases
Vitamins C and E have an important role in protection against ROS
ROS may cause lipid peroxidation and damage to cell membranes and to DNA
ROS is thought to be formed at complex I, II, and III, when electrons cannot be transferred to
the next complex
o When mobile carriers Co-enzyme Q and cytochrome
C cannot deliver their electrons and are thus are fully
occupied with electrons
An imbalance between the generation of ROS and the cell’s
ability to clear oxidants can lead to pathogenic levels of ROS
leading to damage of proteins, lipids, and DNA
Apoptosis is determined through two main interconnected
pathways, which are the:
Intrinsic pathway
o Receptor mediated
o Involving tumour necrosis factor receptors (TNFR)
FAS (CD95)
TRAIL (TNFRSF10)
o Extracellular domain binds to ligand
, Leading to receptor clustering and intracellular recruitment of proteins into a
death-inducing signalling complex (DISC)
Which then activates an initiator caspase, pro-caspase 8 (or 10)
Triggering the execution phase of apoptosis via the activation of the
downstream effector caspase, Caspase 3 (and 6, 7)
Extrinsic pathway
o Can be activated by cellular stresses
o Activation of the intrinsic pathway results in mitochondrial permeabilization
Release of pro-apoptotic proteins
Loss of the mitochondrial (trans) membrane potential (ΔΨm) and
concomitant arrest of the bioenergetic function of the organelle
Two protein categories:
Proteins that can activate the caspase dependent pathway
Other cell death proteins such as apoptosis inducing factor (AIF) and
endonuclease G (Endo G)
Processes that contribute to mitochondrial outer membrane permeabilization (MOMP) and thereby
promote the translocation of mitochondrial intermembrane space proteins:
Prolonged opening of the permeability transition pore (PTP)
Channel formation by pro-apoptotic proteins BAX and BAK1
Direct MOMP effects of pro-apoptotic stimuli
Resistance to apoptosis:
thought to be caused by deregulation of several master switch proteins such as:
o Hypoxia inducible factor-1 (HIF1),
o c-Myc
o TP53
Results in:
o The upregulation of anti-apoptotic proteins
o Suppression of pro-apoptotic proteins
o Silencing of death receptors
o Production of hexokinase II (HKII), which increases the resistance of mitochondrial
permeability transition (MPT)
To prevent cell death, cells have many specific repair and waste disposal/recycle pathways. Cancer
cells adopt and fine-tune these pathways to maintain cell proliferation.
Lysosomes play a central role in waste disposal and recycling pathways
Single membrane organelles
Form an acidic compartment
Involved in cell signalling, membrane repair,
immune response and energy metabolism
Damaged or dysfunctional proteins can be removed by:
Ubiquitin mediated proteosomal degradation
Chaperone mediated autophagocytosis
o Proteins are directed to the lysosome
Lysosomal degradation is also used for breakdown of
components that are taken up by:
Endocytosis
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