Few interesting studies brought this group to investigate the role of LXR in prostate cancer; LXR is involved in lipid metabolism and cholesterol has a role in tumor development, together with LNCaP xenografts in high cholesterol diet mice that showed increase apoptosis and phospho-signaling.
This group connected the dots and investigated LXR activation in LNCaP in vitro and in vivo and showed very nicely the important role of it in contributing to the cancer apoptosis through downregulation of the AKT pathway.
I was a little perplexed why in Figures 3b and 8b they show that T compound nearly obliterates all P-AKT in total cell lysate, yet tons of it is present in the membrane and cytosolic fraction in Figure 7. I guess there is a lot of P-AKT in the plasma membrane that was lost in the pellet during the total cell lysis, which is not sensitive to T compound, nor important in regulating apoptosis? All the other data fits together pretty well, though.
ReplyDeleteI would have liked to have seen Flow Cytometry histograms for subG1 experiments since they are the functional read-outs for the paper. Especially since the subG1 experiment in Figure 8 shows that cholesterol addition reduces the level of apoptosis by restoring P-AKT localization to lipid rafts. This is the key experiment that supports their claim that P-AKT in lipid rafts is mediating cell survival.
This study may be controversial if translated to the clinic. Raising plasma HDL levels in cancer patients can't be good.
Natalie, you raise a good point about the loss of phospho-AKT in the total cell lysate but not the membrane and cytosolic fraction. I think this is actually important to their findings and they base their hypothesis around this observation. They mention that the sub-population of AKT in the rafts, that is cholesterol sensitive, has been shown to phosphorylate distinct substrates. These subtrates they say have been shown to support most of the prosurvival effects of AKT. The LXRs seem to uniquely modulate the lipid raft signaling and the arguably dismiss the membrane-associated AKT. But it is puzzling how it isn't seen in total lysate.
ReplyDeleteI think the paper is an interesting study. I never knew cholesterol and LXRs could affect prostate cancer growth. It makes you wonder about other uncommon relationships between tumor growth and regulators of these important signaling pathways like AKT.
This paper clearly showed that LXR activation impaired the survival of PCa cells, and this is undoubtedly linked with the changes in cholesterol levels, which indirectly affect the AKT signaling. It might be useful to have a comparison between PCa and normal cells and some other cancer cells to see how specific this effect is.
ReplyDeleteAlso to note is that the link with the AKT pathway is not very strong. MyrAKT did not show as much efficiency as cholesterol in reversing the apoptosis induced by T; phospho-AKT is abundant and not affected by T in cyto.+membrane, suggesting more beyond AKT-Phospho is involved.