Simvastatin modulates the adhesion and growth of hepatocellular carcinoma cells via decrease of integrin expression and ROCK

Abstract

Abstract. Hepatocellular carcinoma (HCC) has become a global health concern and is one of the leading causes of cancer death after lung and gastric cancers. It has been suggested that the 3-hydroxy-3-methyl-glutarylcoenzymeCoA (HMG-CoA) reductase inhibitor simvastatin exhibits anticancer properties. To this end, we analyzed the influence of simvastatin on the cell growth and adhesion of HCC and evaluated the yet poorly characterized mechanism of action of simvastatin in HCC. HepG2 and Huh7 cells were treated with simvastatin (16-64 μM) for different time periods. Cell proliferation using the MTT assay and tumor cell adhesion to endothelial cell monolayers were evaluated. ß1, ß3 and ·2 integrin adhesion receptors and the downstream target of simvastatin Rho-dependent kinase (ROCK) were analyzed by Western blot. Further blocking studies with the ROCKinhibitor H1152 and anti-integrin ß1 and ß3 antibodies were carried out. Simvastatin treatment inhibited dose-dependently tumor cell growth and attachment to endothelium. The inhibitory effect of simvastatin on cell adhesion was associated with decreased expression of ß1, ß3 and ·2 integrins. Furthermore, simvastatin strongly reduced the expression of ROCK-I and activated MYPT, an indicator of ROCK activity. Also, the ROCK-inhibitor H1152 reduced the adhesive capacity of the tumor cells. Anti-adhesive effects of simvastatin were prevented by exogenous mevalonate, a downstream product of HMG-CoA. Tumor cell adhesion to endothelium was significantly impaired following incubation with functional anti-ß1 antibody. Simvastatin modifies the expression of cell adhesion molecules leading to reduced tumor cell growth and invasion. These beneficial effects of simvastatin may be mediated by ROCK. The data presented may point to novel treatment options for HCC.

HMG-CoA reductase regulates CCL17-induced colon cancer cell migration via geranylgeranylation and RhoA activation

“…In addition, our results showed that simvastatin decreased CCL17-induced HT-29 cell migration without any concomitant effects on cell proliferation of apoptosis, indicating a direct effect of simvastatin on colon cancer cell migration, which might be of beneficial value. Although this is the first report to show that simvastatin inhibits colon cancer cell migration in response to chemokine signaling, other investigations 11 have found that simvastatin can inhibit migration of breast [21], hepatic [22], renal [17] and prostate [23] cancer cells, supporting the concept that simvastatin is an effective inhibitor of tumor cell migration.…”

Simvastatin sensitizes human gastric cancer xenograft in nude mice to capecitabine by suppressing nuclear factor-kappa B-regulated gene products

“…The potential anti-carcinogenic effects of simvastatin alone or in combination with various anticancer therapies have been documented in a number of tumor cell lines and mouse models, including colorectal [10], hepatocellular [11], prostate [12], breast [13], and hematological malignancies [14]. How simvastatin exerts its anticancer effects is not fully understood, but it has been found to modulate various signaling cascades including mitogen-activated protein kinases [15,16], PI3-K/ Akt [17], NF-κB [18][19][20], STAT3 [14], cell cycle-dependent kinases [21], Rho-dependent kinase [22,23], and Ras-related C3 botulinum toxin substrate 1 [24].…”

Statins: Perspectives in cancer therapeutics

“…Another study showed, using the same cell lines, that simvastatin induced apoptosis, G0/G1 cell cycle arrest, suppressed CDKs and up--regulated p19 and p27 [71]. The authors further showed that simvastatin suppressed cell adhesion, paralleled by a decrease of B1, B2 and A3 integrins and a strong suppression of ROCK--I in these cell lines [71]. Treatment of Huh--7 HCC cells by lovastatin induced apoptosis, an effect that was further amplified by enzastaurin, a PKC--β inhibitor, in a strategy developed to counteract the inductive effect of lovastatin on this enzyme [72].…”

“…In addition, co--treatments of HepG2 cells with EPA and lovastatin, two separate classes of HMG--CoA reductase inhibitors, amplified cell growth arrest, as compared to lovastatin alone [70]. Another study showed, using the same cell lines, that simvastatin induced apoptosis, G0/G1 cell cycle arrest, suppressed CDKs and up--regulated p19 and p27 [71]. The authors further showed that simvastatin suppressed cell adhesion, paralleled by a decrease of B1, B2 and A3 integrins and a strong suppression of ROCK--I in these cell lines [71].…”