Unearthing the Janus-face cholesterogenesis pathways in cancer

• Published in: Biochemical pharmacology 2022-02, Vol.196, p.114611-114611, Article 114611
• Main Authors: Madan, Babita, Virshup, David M., Nes, W. David, Leaver, David J.
• Format: Article
• Language: English
• Subjects: Animals; Anticholesteremic Agents - therapeutic use; Antineoplastic Agents - therapeutic use; Benzylamines - pharmacology; Benzylamines - therapeutic use; Cancer; Cholesterol - metabolism; Cholesterol biosynthesis; Cholesterol biosynthesis inhibitors; Humans; Lanosterol - analogs & derivatives; Lanosterol - pharmacology; Lanosterol - therapeutic use; Neoplasms - drug therapy; Neoplasms - metabolism; Sterol enzymes/genes; Structure-function; Terbinafine - pharmacology; Terbinafine - therapeutic use; Thiophenes - pharmacology; Thiophenes - therapeutic use
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2021.114611

[Display omitted] Cholesterol biosynthesis, primarily associated with eukaryotes, occurs as an essential component of human metabolism with biosynthetic deregulation a factor in cancer viability. The segment that partitions between squalene and the C27-end cholesterol yields the main cholesterogenesis branch subdivided into the Bloch and Kandutsch-Russell pathways. Their importance in cell viability, in normal growth and development originates primarily from the amphipathic property and shape of the cholesterol molecule which makes it suitable as a membrane insert. Cholesterol can also convert to variant oxygenated product metabolites of distinct function producing a complex interplay between cholesterol synthesis and overall steroidogenesis. In this review, we disassociate the two sides of cholesterogenesisis affecting the type and amounts of systemic sterols—one which is beneficial to human welfare while the other dysfunctional leading to misery and disease that could result in premature death. Our focus here is first to examine the cholesterol biosynthetic genes, enzymes, and order of biosynthetic intermediates in human cholesterogenesis pathways, then compare the effect of proximal and distal inhibitors of cholesterol biosynthesis against normal and cancer cell growth and metabolism. Collectively, the inhibitor studies of druggable enzymes and specific biosynthetic steps, suggest a potential role of disrupted cholesterol biosynthesis, in coordination with imported cholesterol, as a factor in cancer development and as discussed some of these inhibitors have chemotherapeutic implications.