Question

Membrane Fluidity & Apoptosis

Depletion of cholesterol in the cell membrane using drug (mevastatin) has been associated with apoptosis in cancer cells.

a. What effect would cholesterol depletion have on the integrity of lipid rafts in the membrane? Rubric (2): what will happen to lipid rafts if there is less cholesterol?

b. Researchers found that FAS death receptor was activated in cholesterol depleted cancer cells. Explain how activation of this receptor activates killer caspases. Rubric (4): explain al downstream events after activation of death receptor and stopping with how activation of execution caspases occurs.

c. FAS death receptor is localized to lipid rafts! So what is your conclusion as to why mevastatin initiates apoptosis in cancer cells? Rubric (3): conclusion is complete and correct.

Answer 1

A) Lipid rafts are mainly composed of cholesterol and sphingolipids, which play a vital role in the cellular signalling pathways. Mevastatin, is a inhibitor of cholesterol biosynthesis, which decrease the cholesterol level in the lipid rafts. This lead to the activation of protein kinases, death receptor kinases, inactivation of Akt kinases, etc. which leads to apoptosis.

B) The cell membrane consist if the death receptor such as Fas, TNF receptor, etc. which involves in the extriniscpathway of apoptosis. Once suitable ligand binds to this receptor, trimerisation of the cytoplasmic domain(death domain) occur which leads to formation of Fas-associated Death Domain which cleaves inactive procaspase 8 to active caspase-8 forming a Death Inducing Signaling Complex. this caspase-8 will inturn cleaves other executioner caspase-3,6,7. At times, the caspase-8 cleave Bid to t-Bid, which induces mitochrondrial stress, thereby activating executioner caspase leading to cell death.

C) Mevastatin, is a inhibitor of HMG-CoA reductase enzyme. It is the key enzyme which involves in the biosynthesis of cholesterol.Mevastatin involves in reducing cell proliferaiton, decreasing cell signalling,etc. It also involves in the translocation of various proapoptotic proteins and inducing intrinisic cell death. Moreover, the drug has the property of antiproliferation.These property makes the cancer cells to undergo apoptosis.