How Statins May Affect the Molecular Pathogenesis of HCC
During disease development, cancer cells acquire multiple key biological capabilities conferring them a competitive survival advantage and culminating in invasion and metastasis. Whether the pathogenesis of HCC is strongly etiology-dependent remains unproven. In any case, fully integrated direct (genome instability leading to mutations occurring in single or multiple oncogenes or tumor suppressor genes) and indirect oncogenic mechanisms (liver inflammation, regeneration and cirrhosis)[10,12] are likely to concur to a variable extent in the development of disease in the individual patient.
Karyotype Abnormalities Karyotype abnormalities, the morphological hallmark of genetic instability, have been consistently described in human HCC, structural chromosomal abnormalities being found predominantly in the pericentromeric region and in advanced tumors. Key cellular functions are inhibited by statins selectively in various karyotypically abnormal cell types (including colorectal and ovarian cancer cells and human embryonic stem cells, which possess neoplastic-like properties) and this is mediated via a suppression of the stemness pathway.[14,15]
Lipogenic Pathways Low serum levels of either LDL- or total-cholesterol[5,17] are major risk factors for HCC suggesting that HCC itself hi-jacks cholesterol away from the bloodstream because its growth is critically cholesterol-dependent. HCC displays perturbed cholesterol metabolism both within mitochondria and in cell membranes. In human HCC, a relatively higher cell membrane cholesterol content contributes to increasing membrane rigidity. This, in turn, alters membrane signal transduction pathways leading to favored cell proliferation. Increased cholesterol levels in mitochondria from either rat or human HCC cells contribute to chemotherapy resistance and cholesterol depletion by inhibition of hydroxymethylglutaryl-CoA reductase enhances sensitivity to chemotherapy.
Cell Growth/Survival Pathways The proto-oncogene myc (c-myc) codes for a nuclear protein, which controls nucleic acid metabolism and mediates the cellular response to growth factors. The human c-myc gene plays a pivotal role in liver oncogenesis. Truncation of the first exon, which regulates the expression of c-myc, is crucial for tumorigenicity. Given that HMG-CoA reductase is a critical regulator of MYC phosphorylation, activation, and tumorigenic properties, the inhibition of this enzyme by statins may be a useful target for the treatment of MYC-associated HCC. Consistently atorvastatin blocks both MYC phosphorylation and activation and suppresses tumor initiation and growth both in a transgenic model of MYC-induced HCC as well as in cell lines derived from human HCC. The specificity of these findings was proven by showing that the antitumor effects of atorvastatin were blocked by co-administering mevalonate, the product of HMG-CoA reductase.
Cell Proliferation, Differentiation and Angiogenesis IL-6-STAT3 Pathway As a gender-dependent risk factor for HCC explaining why females are less prone to liver cancer than males,[12,23] IL-6 is a HCC bio-marker and an ideal molecular target to be aimed at. IL-6 activates the transcription factor STAT3 (signal transducer and activator of transcription 3), an acute-phase response factor, which is next phosphorylated by the receptor associated kinases, and then forms homo- or hetero-dimers that translocate to the cell nucleus where it acts as a transcription activator. STAT-3 directly affects cell proliferation, differentiation and angiogenesis. Thus, the dysregulation of the STAT-3 pathway, which follows HCV infection may take part in HCC development at an early stage of hepatocyte dysplasia. Moreover, STAT3 is a major pathway which mediates signals from IL-6 to the nucleus. At this level, where different genes associated with proliferation and apoptosis are regulated, IL-6 induces cell survival upon drug treatment in HCC cells; a feature that is blunted by inhibition of IL-6/STAT3 pathway. Therefore, it is of major interest that statins reduce IL-6-induced C-reactive protein (CRP) production directly in hepatocytes via inhibition of protein geranylgeranylation. While the potential of STAT-3 as a therapeutic target in different neoplasms has recently been highlighted,[29,30] evidence that statins might affect STAT3 pathway mainly comes from vascular rather than oncology studies[31,32] and therefore further research is required.
Apoptosis Apoptosis is a key mechanism leading to disposal of unwanted, senescent, or damaged cells and therefore plays a major role in cell health and disease. The development and growth of HCC are heralded by overexpression of anti-apoptotic genes permitting cell survival and neoangiogenesis. Thus, strategies aimed at inducing apoptosis might be exploited to manage HCC.[33,34] In one study simvastatin induced overexpression of the pro-apoptotic gene Bax together with an inhibition of BCL-2, the gene that has the well-known function of protecting cells from apoptosis. Interestingly, the simvastatin-mediated induction of apoptosis occurs selectively in cancer cells but not in normal cells.
Cell Migration and Metastasis Rho-dependent pathway is a mechanism promoting cancer cell migration and metastasis.[36,37] Rho small GTPases, cycle between a guanosine triphosphate (GTP)-bound active and a guanosine diphosphate (GDP)-bound inactive conformation and it is the intracellular GTP/GDP-bound forms ratio that works as molecular switch that controls a wide variety of signal transduction pathways.[38,39] Once activated, the Rho protein promotes cell motility via assembly of the actin-myosin contractile filaments. Increased expression of RhoC is linked to increased invasion in various cancer types, including HCC, in which it is a marker of ominous prognosis,[40,41] a risk factor for metastasis and a candidate molecular target for therapy. In reviewing the role of statins in gastrointestinal cancer, Bhuket and Higgins have highlighted that the interaction of prenylated proteins with cell membranes (Fig. 3) is essential for the activity of signaling of the G proteins Ras and Rho, which are involved in cancerigenesis Interestingly, simvastatin treatment inhibits tumor cell growth and adhesion to endothelium in HepG2 and Huh7 cells in a dose-dependent manner, mediated by decreased expression of integrins and ROCK-I.
Chemical basis for cancer prevention of statins. By inhibiting Hydroxy-Methyl-Glutaryl-Coenzyme A (HMGCoA) Reductase activity, statins block the synthesis of mevalonate, the precursor molecule of cholesterol, ubiquinone and prenyl groups (i.e. farnesyl and geranylgeranyl). Prenylation of proteins is required for their attachment to cell membrane which, in turn, is essential for the signaling of G proteins Ras and Rho.43 Permission obtained to reproduce from Bhuket Nature Clin Pract Gastro Hepatol 2006. Confirmation number 11019142 Order Date 08/09/2012.
Taken collectively, data summarized in this chapter are the molecular basis accounting for the findings observed both in animal studies and in humans discussed next.
Statins Inhibit Primary and Metastatic HCC: Evidence From in vitro and in vivo Experimental Studies
Several experimental studies, summarized in Table 1[22,45–54] support that statins have an inhibitory effect on primary and metastatic HCC. Analysis of these studies pinpoints that the anticancer effect of statins may be more intensive when given pre- and post-implantation of cancer. Such an effect is dose-dependent and more evident in metastases, occurs via increased apoptosis, arrest of the cell cycle, endoplasmic reticulum (ER) stress response, leading to autophagy, and is partly due to the pleiotropic action of statins being mediated by inhibition of synthesis of ubiquinone. Of potential clinical interest, anticancer activity of statins may be potentiated by either enzastaurin, an inhibitor of PKC (deemed to be the receptor protein of tumor-promoting phorbol esters) or celecoxib, a cyclooxygenase-2 (COX-2)-specific inhibitor that blocks the synthesis of prostaglandins from arachidonic acid. Of major importance, further to hepatocytic cells, endothelial cells are an elective target of the action of statins as well. Such an additional cell target accounts for the combined activity against both cancer and portal hypertension shown by statins, which will be discussed in detail in paragraph on gastrointestinal hemorrhage.
J Gastroenterol Hepatol. 2012;27(11):1654-1664. © 2012 Blackwell Publishing