The Ras/MAPK pathway and hepatocarcinoma: pathogenesis and therapeutic implications.

BACKGROUND: Hepatocellular carcinoma (HCC) is still a major health problem, often diagnosed at an advanced stage. The multikinase inhibitor sorafenib is to date the sole approved systemic therapy. Several signalling pathways are implicated in tumour development and progression. Among these pathways, the Ras/MAPK pathway is activated in 50-100% of human HCCs and is correlated with a poor prognosis. The aim of this work was to review the main intracellular mechanisms leading to aberrant Ras pathway activation in HCC and the potential therapeutic implications. MATERIALS AND METHODS: This review is based on the material found on PubMed up to December 2014. 'Ras signaling, Ras dysregulation, Ras inhibition, MAPK pathway, cancer, hepatocarcinoma and liver cancer' alone or in combination were the main terms used for online research. RESULTS: Multiple mechanisms lead to the deregulation of the Ras pathway in liver cancer. Ras and Raf gene mutations are rare events in human hepatocarcinogenesis in contrast to experimental models in rodents. Downregulation of several Ras/MAPK pathway inhibitors such as GAPs, RASSF proteins, DUSP1, Sprouty and Spred proteins is largely implicated in the aberrant activation of this pathway in the context of wild-type Ras and Raf genes. Epigenetic or post-transcriptional mechanisms lead to the downregulation of these tumour suppressor genes. CONCLUSION: Ras/MAPK pathway effectors may be considered as potential therapeutic targets in the field of HCC. In particular after the arrival of sorafenib, more Ras/MAPK inhibitors have emerged and are still in preclinical or clinical investigation for HCC therapy.

The small GTPases regulate HMC05-induced NQO-1 expression with an antioxidant effect in smooth muscle cells.

Recently, Banhabackchulchunmatang (HMC05) has been implicated as a preventive and/or therapeutic candidate for cardiovascular diseases due to its inhibition of atherosclerosis lesions and its reduction of neointima formation. Knowledge of the mechanism of HMC05 in smooth muscle cells (SMC) is limited. However, SMC may be a potential target for HMC05 therapy because they are supported by the HMC05-mediated preservation of medial smooth muscle cell layers in pathogenic progression. Therefore, in the present study, we hypothesized that the effect of HMC05 is associated with reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H):quinone oxidoreductase-1 (NQO-1) gene regulation, which precipitates an antioxidant effect in SMC. HMC05 significantly increased NQO-1 gene expression in a dose- and time-dependent manner. The reactive oxygen species-mediated toxicity that was generated by xanthine/xanthine oxidase was suppressed by HMC05. The knockdown of the NQO-1 gene abrogated the HMC05-mediated cytoprotection. Interestingly, pretreatment with a chemical inhibitor of geranylgeranyl transferase 1 or farnesyl transferase abolished the NQO-1 gene induction and cytoprotection by HMC05. The transfection of dominant negative RhoA or Ras suppressed HMC05-induced gene expression. Berberine and hesperidin, which are found in large quantities in HMC05, also induced NQO-1 gene expression. Taken together, this is the first study to demonstrate that HMC05 is efficacious in protection against oxidative stress through NOQ-1 gene induction via the regulation of RhoA and/or Ras, and that berberine and hesperidin are major components of NQO-1 gene induction. This study provides mechanistic targets of HMC05 in reducing atherosclerotic lesions in atherosclerosis.

Genetic and pharmacological inhibition of Rheb1-mTORC1 signaling exerts cardioprotection against adverse cardiac remodeling in mice.

A previous study indicated that Rheb1 is required for mammalian target of TOR complex 1 (mTORC1) signaling in the brain. However, the function of Rheb1 in the heart is still elusive. In the present study, we deleted Rheb1 specifically in cardiomyocytes and found that reduced Rheb1 levels conferred cardioprotection against pathologic remodeling in myocardial infarction (MI) and pressure overload (transverse aortic constriction) mouse models. Cardiomyocyte apoptosis was reduced and mTORC1 activity was suppressed in cardiomyocyte Rheb1-deletion mice, suggesting that Rheb1 regulates mTORC1 activation in myocardium. Furthermore, we demonstrated that astragaloside IV (As-IV) could inhibit mTORC1, and As-IV treatment displayed similar protection against MI and transverse aortic constriction as Rheb1 genetic inhibition. This study indicates that Rheb1 is essential for mTORC1 activation in cardiomyocytes and suggests that targeting Rheb1-mTORC1 signaling, such as by As-IV treatment, may be an effective therapeutic method for treating patients with adverse cardiac remodeling after MI and hypertrophy.

Biochemical and biological characterization of tumor-associated mutations of p110alpha.

Signaling by class I phosphatidylinositol 3-kinase (PI3K) controls cell growth, replication, motility, and metabolism. The PI3K pathway commonly shows gain of function in cancer. Two small GTPases, Rheb (Ras homolog enriched in brain) and Ras (rat sarcoma viral oncogene), play important roles in PI3K signaling. Rheb activates the TOR (target of rapamycin) kinase in a GTP-dependent manner; it links TOR to upstream signaling components, including the tuberous sclerosis complex (TSC) and Akt (homolog of the Akt8 murine lymphoma viral oncoprotein). Constitutively active, GTP-bound Rheb is oncogenic in cell culture, and activity that requires farnesylation. Ras activates PI3K by recruitment to the plasma membrane and possibly by inducing a conformational change in the catalytic subunit p110 of PI3K. In return, Ras signaling through the MAP kinase (MAPK) pathway is activated by PIP(3), the product of PI3K. Loss of Ras function can interfere with PI3K signaling. Various lines of evidence suggest complementary roles for PI3K and MAPK signaling in oncogenesis.