Abstract
The mevalonate pathway provides sterols for membrane structure and nonsterol intermediates for the post-translational modification and membrane anchorage of growth-related proteins, including the Ras, Rac, and Rho GTPase family. Mevalonate-derived products are also essential for the Hedgehog pathway, steroid hormone signaling, and the nuclear localization of Yes-associated protein and transcriptional co-activator with PDZ-binding motif, all of which playing roles in tumorigenesis and cancer stem cell function. The phosphatidylinositol-4,5-bisphosphate 3-kinase-AKT-mammalian target of rapamycin complex 1 pathway, p53 with gain-of-function mutation, and oncoprotein MYC upregulate the mevalonate pathway, whereas adenosine monophosphate-activated protein kinase and tumor suppressor protein RB are the downregulators. The rate-limiting enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), is under a multivalent regulation. Sterol regulatory element binding protein 2 mediates the sterol-controlled transcriptional downregulation of HMGCR. UbiA prenyltransferase domain-containing protein-1 regulates the ubiquitination and proteasome-mediated degradation of HMGCR, which is accelerated by 24, 25-dihydrolanosterol and the diterpene geranylgeraniol. Statins, competitive inhibitors of HMGCR, deplete cells of mevalonate-derived intermediates and consequently inhibit cell proliferation and induce apoptosis. Clinical application of statins is marred by dose-limiting toxicities and mixed outcomes on cancer risk, survival and mortality, partially resulting from the statin-mediated compensatory upregulation of HMGCR and indiscriminate inhibition of HMGCR in normal and tumor cells. Tumor HMGCR is resistant to the sterol-mediated transcriptional control; consequently, HMGCR is upregulated in cancers derived from adrenal gland, blood and lymph, brain, breast, colon, connective tissue, embryo, esophagus, liver, lung, ovary, pancreas, prostate, skin, and stomach. Nevertheless, tumor HMGCR remains sensitive to isoprenoid-mediated degradation. Isoprenoids including monoterpenes (carvacrol, L-carvone, geraniol, perillyl alcohol), sesquiterpenes (cacalol, farnesol, β-ionone), diterpene (geranylgeranyl acetone), “mixed” isoprenoids (tocotrienols), and their derivatives suppress the growth of tumor cells with little impact on non-malignant cells. In cancer cells derived from breast, colon, liver, mesothelium, prostate, pancreas, and skin, statins and isoprenoids, including tocotrienols, geraniol, limonene, β-ionone and perillyl alcohol, synergistically suppress cell proliferation and associated signaling pathways. A blend of dietary lovastatin and δ-tocotrienol, each at no-effect doses, suppress the growth of implanted murine B16 melanomas in C57BL6 mice. Isoprenoids have potential as adjuvant agents to reduce the toxicities of statins in cancer prevention or therapy.
Highlights
Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway (Goldstein and Brown, 1990)
Synergistic effect on eliminating cancer stem-like cells, ↓mammosphere formation and pStat-3 signaling; mevalonate attenuated the effect of the blend Synergistic effect on cell proliferation and membrane RhoA; effects were attenuated by mevalonate; tocotrienol attenuated statin-induced upregulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) Synergistic effect on Ras prenylation, DNA synthesis, cell proliferation and free and esterified cholesterol Synergistic effect on cell viability, cell cycle, ↓HMGCR, ↓p-extracellular signalregulated kinase (ERK)/ERK; ↑caspase-3 Synergistic effect on cell growth
The widely prescribed statins, originally designed for hypercholesterolemia, hold promises for cancer therapy as the multiple roles of the mevalonate pathway in growth support and regulation unfold. The repurposing of this class of wellestablished drugs for cancer stems from their ability to deplete mevalonate-derived sterol and nonsterol products essential for the prenylation of proteins involved in growth regulation and signaling pathways for cell proliferation
Summary
Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway (Goldstein and Brown, 1990). Prescribed as hypocholesterolemic agents, statins have been shown to inhibit cell proliferation and induce apoptosis in preclinical studies (Clendening and Penn, 2012). Dose-limiting toxicities of statins attributable to statin-induced compensatory upregulation of HMGCR and indiscriminate inhibition of HMGCR in normal and tumor cells pose constraints on the application of statins in cancer and call for novel approaches in reducing their side effects. The multivalent regulation of HMGCR, including sterol-mediated transcriptional downregulation and nonsterol-induced enhancement of degradation, in normal cells contrasts with the sterol-resistant, dysregulated tumor HMGCR that remains uniquely sensitive to isoprenoid-mediated downregulation (Mo and Elson, 2004). The mechanisms underlying the isoprenoid-mediated tumor suppression is elucidated, followed by studies showing the synergistic effect of statins and isoprenoids and suggesting the potential of isoprenoids in adjuvant therapy to reduce the toxicities of statins
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