Differential Expressions of p53, p53R2, hRRM2 and PBR in Chronic Lymphocytic Leukemia: A Correlation with Intracellular Cholesterol

Abstract

Regulation of intracellular cholesterol homeostasis exists under balance between intracellular biosynthesis and uptake from extracellular origin by cell surface transport proteins. Expected role of cholesterol on either tumor suppressor gene and/or DNA synthesis has been aimed in the present study to explore intracellular cholesterol homeostasis in CLL subjects. Higher expressions of p53R2 (p53 dependent subunit of ribonucleotide reductase) and p53 were found in lymphocytes of chronic human lymphocytic leukemia as comparison to their normal counterparts. Inverse relation was found with p53 independent R2 subunit (in human hRRM2) of ribonucleotide reductase, which was found to be decreased from its control group. More expression of peripheral type benzodiazepine receptor, a cholesterol transporter, was noticed in isolated nuclear fraction with simultaneous increase of cholesterol concentration in cytoplasmic and nuclear compartments. A parallel increase of cholesterol in cell nucleus with increased p53R2 expression shows priority of the involvement of cholesterol in the process of cell replication.

Atherosclerosis and carcinoma: Two facets of dysfunctional cholesterol homeostasis

“…This triggers vascular hypercholesterolemia, atherosclerosis, and related complications. On the other hand, if the cytoplasm is not getting saturated due to the passage of cholesterol into the cell nucleus, [38,39,[42][43][44] the LDLR remains overexpressed and in functional mode. This makes for continuous cholesterol entry into the cell and cell nucleus, triggering cell proliferation through the activation of cell cycle proteins.…”

“…Conversely, the low profile of nuclear PBR, [50,[77][78][79] or in other words blocked PBR, does not allow enough cholesterol to enter into the cell nucleus and hence defeats cell multiplication by depressing cell cycle protein expression ( Figure 4B). This emphasizes the fact that overexpression of PBR [50,77] and the high cholesterol concentration [42][43][44] in cancer tumor cells may be the reason for uncontrolled cell proliferation in tumor tissues.…”

“…[38] Our studies have also shown that the cytoplasm and cell nucleus of tumor cells contain a greater cholesterol concentration as compared to normal cells. [42][43][44] In the first decade of this 21st century, the finding of a peripheral benzodiazepine receptor (PBR; other name: translocator protein or TSPO) as a cholesterol port on the nuclear membrane (previously it was known only on the mitochondrial membrane) was considered as new insight into its pivotal role in cell proliferation and cell differentiation. [75,76] The existence of PBR at the nuclear subcellular location in an aggressive breast cancer cell line [50] and human glioma cells [77] has been contemplated for its link in cell proliferation.…”

“…Recent work in our laboratory also monitored the impact of cholesterol in cell cycle operation [38,39] and cancer cell progression. [40][41][42][43][44][45] In cancer tumor cells, the cholesterol pool is not under the control of intracellular sterol regulatory element-binding protein (SREBP)-mediated feedback regulation [46][47][48] to maintain cholesterol homeostasis [49] and gets accumulated within cell nucleus by crossing the nuclear membrane possibly through peripheral type benzodiazepine receptor and promotes cell proliferation. [38,44,50,51] In the precancerous stage, the immune cells also die because of a lack of requisite concentration of cytosolic and nuclear cholesterol in the intracellular pool, [40,41] preferably from the interference of cholesterol transport by carcinogens across the nuclear membrane.…”

Differential response of T cells to an immunogen, a mitogen and a chemical carcinogen in a mouse model system

“…Since last two decades, various studies have linked cholesterol with tumor growth showing the presence of cholesterol in chromosomal territory and its excess accumulation in the nucleus of cancer cells . The intracellular pool of cholesterol is maintained by de novo cholesterogenesis and low‐density lipoprotein receptor (LDLR)‐mediated endocytosis of cholesterol‐rich low density lipoprotein (LDL) particles.…”