Deterministic Coupling between Cellular Bioenergetics, Cholesterol Synthesis, Cell Proliferation and Cancer

Extensive studies from my laboratory when considered in context with a broad spectrum of work by others, collectively emphasize that an obligatory coupling occurs between the following metabolic phenomena in rapidly growing cells and tumors: 1. There is an enhanced rate of citrate export from tumor mitochondria, concomitant with a pattern for terminal respiration that is consistent with the operation of a “truncated Krebs cycle”; 2. There is an enhanced precursor carbon flux (from cytoplasmic citrate or acetyl-CoA) through the tumor’s cholesterogenic pathway, the cause of which appears to depend upon two characteristic enzymatic aberrations: the expression, per tumor cell, of a dramatically increased (and persisting) amount of HMGR, and an equally increased activity of ATP-citrate lyase; and, 3. A recently discovered set of acidic, isoprenylated (or terpenylated) phospho-proteins arises in proliferating cells (tumor or “normal”), whose synthesis prior to and during the S-phase of the cell cycle mandates a highly active and continuous formation and utilization of cholesterogenic pathway intermediates, especially those generated in the the segment between mevalonic acid and squalene.