The tobacco-specific carcinogen-operated calcium channel promotes lung tumorigenesis via IGF2 exocytosis in lung epithelial cells.

Nicotinic acetylcholine receptors (nAChRs) binding to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces Ca signalling, a mechanism that is implicated in various human cancers. In this study, we investigated the role of NNK-mediated Ca signalling in lung cancer formation. We show significant overexpression of insulin-like growth factors (IGFs) in association with IGF-1R activation in human preneoplastic lung lesions in smokers.

CD44 expression contributes to trastuzumab resistance in HER2-positive breast cancer cells.

Resistance to HER2-targeted therapies remains a major obstacle in the treatment of HER2-overexpressing breast cancer. CD44, a putative breast cancer stem cell (CSC) marker, is overexpressed in trastuzumab-resistant breast cancer cells. While CSC-related genes may play a role in the development of trastuzumab resistance, conflicting results have been published about CSC response to trastuzumab.

HER family kinase domain mutations promote tumor progression and can predict response to treatment in human breast cancer.

Resistance to HER2-targeted therapies remains a major obstacle in the treatment of HER2-overexpressing breast cancer. Understanding the molecular pathways that contribute to the development of drug resistance is needed to improve the clinical utility of novel agents, and to predict the success of targeted personalized therapy based on tumor-specific mutations. Little is known about the clinical significance of HER family mutations in breast cancer.

Transcriptional and posttranslational regulation of insulin-like growth factor binding protein-3 by Akt3.

Insulin-like growth factor (IGF)-dependent and -independent antitumor activities of insulin-like growth factor binding protein-3 (IGFBP-3) have been proposed in human non-small cell lung cancer (NSCLC) cells. However, the mechanism underlying regulation of IGFBP-3 expression in NSCLC cells is not well understood. In this study, we show that activation of Akt, especially Akt3, plays a major role in the mRNA expression and protein stability of IGFBP-3 and thus antitumor activities of IGFBP-3 in NSCLC cells.

Serum CD44 levels and overall survival in patients with HER2-positive breast cancer.

CD44 is an adhesion molecule involved in tumor cell invasion and metastasis. The function of CD44 in breast cancer is not understood completely, or is its role as a predictive or prognostic factor. In this study, we tested for the hypothesis that the concentration of soluble CD44 (sCD44) in serum is correlated with clinicopathological factors, especially HER2, and survival in patients with breast cancer.

Fatty acid synthase phosphorylation: a novel therapeutic target in HER2-overexpressing breast cancer cells.

Introduction: The human epidermal growth factor receptor 2 (HER2) is a validated therapeutic target in breast cancer. Heterodimerization of HER2 with other HER family members results in enhanced tyrosine phosphorylation and activation of signal transduction pathways. HER2 overexpression increases the translation of fatty acid synthase (FASN), and FASN overexpression markedly increases HER2 signaling, which results in enhanced cell growth.

Elevated epithelial insulin-like growth factor expression is a risk factor for lung cancer development.

Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling has been implicated in several human neoplasms. However, the role of serum levels of IGFs in lung cancer risk is controversial. We assessed the role of tissue-derived IGFs in lung carcinogenesis.

Cross-talk between the ErbB/HER family and the type I insulin-like growth factor receptor signaling pathway in breast cancer.

Understanding the molecular mechanisms involved in tumorigenesis and their influence on clinical outcome is providing specific molecular markers for targeted therapy. Activation of tyrosine kinase receptors from the human epidermal growth factor receptor family (EGFR, HER2, HER3, HER4) and the insulin-like growth factor receptor I (IGF-IR) plays a key role in the initiation and progression of breast cancer. HER2 overexpression is a validated therapeutic target, as shown by the clinical efficacy of trastuzumab and lapatinib.

Survivin expression in normal human bronchial epithelial cells: an early and critical step in tumorigenesis induced by tobacco exposure.

The inhibitor of apoptosis protein survivin is selectively expressed in tumor cells. The tobacco component nicotine increases the transcription of the survivin gene in non-small cell lung cancer cells. However, the role of survivin expression induced by tobacco component is not clear during lung carcinogenesis.

Insulin-like growth factor-I receptor signaling pathway induces resistance to the apoptotic activities of SCH66336 (lonafarnib) through Akt/mammalian target of rapamycin-mediated increases in survivin expression.

Although preclinical studies have suggested that farnesyltransferase inhibitors (FTI) have promising antitumor activity, clinical trials have shown that FTI activity in patients is actually limited. The mechanism that induces resistance to FTI treatment is still not fully understood. The FTI SCH66336 has been shown to induce apoptotic and antiangiogenic activities in a subset of head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) cell lines.

Implication of AMP-activated protein kinase and Akt-regulated survivin in lung cancer chemopreventive activities of deguelin.

Survivin plays important roles in maintaining cell proliferation and survival and promoting tumorigenesis. The present study was conducted to determine the stage of lung carcinogenesis at which survivin expression is induced and to investigate how survivin affects the chemopreventive action of deguelin. In in vitro studies, we observed higher levels of survivin expression in a subset of premalignant and malignant human bronchial epithelial (HBE) and non-small-cell lung cancer (NSCLC) cell lines than in normal HBE cells, and in in vivo studies, a higher level of survivin expression in specimen of human lung dysplasia than in normal lung specimens.

Identification of novel antiangiogenic anticancer activities of deguelin targeting hypoxia-inducible factor-1 alpha.

Hypoxia-inducible factor 1 (HIF-1) plays an essential role in tumor angiogenesis and growth by regulating the transcription of several genes in response to hypoxic stress and changes in growth factors. This study was designed to investigate the effects of deguelin on tumor growth and angiogenesis, and the mechanisms underlying the antitumor activities of deguelin. We show here that orally administered deguelin inhibits tumor growth and blocks tumor angiogenesis in mice.

Structural basis for depletion of heat shock protein 90 client proteins by deguelin.

Background: The molecular chaperone heat shock protein 90 (Hsp90) participates in preserving the expression and activity of various oncoproteins, including hypoxia-inducible factor 1alpha (HIF-1alpha) and Akt. Deguelin is a rotenoid with antitumor activities. We investigated whether the antitumor activities of deguelin involve the functional inhibition of Hsp90.

5-Aminoimidazole-4-carboxamide riboside suppresses lipopolysaccharide-induced TNF-alpha production through inhibition of phosphatidylinositol 3-kinase/Akt activation in RAW 264.7 murine macrophages.

5-Aminoimidazole-4-carboxamide riboside (AICAR) is an adenosine analog and a widely used activator of AMP-activated protein kinase (AMPK). We examined the effect of AICAR on LPS-induced TNF-alpha production in RAW 264.7 and peritoneal macrophages and its molecular mechanism in RAW 264.

Differential regulation of phosphatidylinositol 3-kinase/Akt, mitogen-activated protein kinase, and AMP-activated protein kinase pathways during menadione-induced oxidative stress in the kidney of young and old rats.

We investigated regulation of various signal transduction pathways during oxidative stresses in the kidney of young and aged rats. Menadione-induced regulation of molecules in PI 3-kinase, MAPK, and AMPK pathways was determined in the young (2 months) and old (24 months) groups. PI 3-kinase activity and Akt phosphorylation were significantly reduced in the old compared with the young.

Tetrandrine cytotoxicity and its dual effect on oxidative stress-induced apoptosis through modulating cellular redox states in Neuro 2a mouse neuroblastoma cells.

Tetrandrine (TET), a plant alkaloid, is known primarily as a non-selective Ca(2+) channel blocker. On the contrary to the cytoprotective effect on ischemia/reperfusion injury, TET has also been reported to cause cytotoxicity. In this study, we wished to understand the apparently disparate effects of this potential drug and thus investigated molecular mechanisms on proliferation and apoptosis and its effect on oxidative stress-induced apoptosis in Neuro 2a mouse neuroblastoma cells.