Gaoliang Ouyang

The activation of Akt/PKB signaling pathway and cell survival

Akt/PKB is a serine/threonine protein kinase that functions as a critical regulator of cell survival and proliferation. Akt/PKB family comprises three highly homologous members known as PKBα/Akt1, PKBβ/Akt2 and PKBγ/Akt3 in mammalian cells. Similar to many other protein kinases, Akt/PKB contains a conserved domain structure including a specific PH domain, a central kinase domain and a carboxyl‐terminal regulatory domain that mediates the interaction between signaling molecules. Akt/PKB plays important roles in the signaling pathways in response to growth factors and other extracellular stimuli to regulate several cellular functions including nutrient metabolism, cell growth, apoptosis and survival. This review surveys recent developments in understanding the molecular mechanisms of Akt/PKB activation and its roles in cell survival in normal and cancer cells.

Periostin potently promotes metastatic growth of colon cancer by augmenting cell survival via the Akt/PKB pathway

Molecular mechanisms associated with tumor metastasis remain poorly understood. Here we report that acquired expression of periostin by colon cancer cells greatly promoted metastatic development of colon tumors. Periostin is overexpressed in more than 80% of human colon cancers examined with highest expression in metastatic tumors. Periostin expression dramatically enhanced metastatic growth of colon cancer by both preventing stress-induced apoptosis in the cancer cells and augmenting endothelial cell survival to promote angiogenesis. At the molecular level, periostin activated the Akt/PKB signaling pathway through the alpha(v)beta(3) integrins to increase cellular survival. These data demonstrated that the survival-promoting function is crucial for periostin to promote tumor metastasis of colon cancer.

Role of hypoxia in the hallmarks of human cancer

Hypoxia has been recognized as one of the fundamentally important features of solid tumors and plays a critical role in various cellular and physiologic events, including cell proliferation, survival, angiogenesis, immunosurveillance, metabolism, as well as tumor invasion and metastasis. These responses to hypoxia are at least partially orchestrated by activation of the hypoxia‐inducible factors (HIFs). HIF‐1 is a key regulator of the response of mammalian cells to oxygen deprivation and plays critical roles in the adaptation of tumor cells to a hypoxic microenvironment. Hypoxia and overexpression of HIF‐1 have been associated with radiation therapy and chemotherapy resistance, an increased risk of invasion and metastasis, and a poor clinical prognosis of solid tumors. The discovery of HIF‐1 signaling has led to a rapidly increasing understanding of the complex mechanisms involved in tumor hypoxia and has helped greatly in screening novel anticancer agents. In this review, we will first introduce the cellular responses to hypoxia and HIF‐1 signaling pathway in hypoxia, and then summarize the multifaceted role of hypoxia in the hallmarks of human cancers. J. Cell. Biochem. 107: 1053–1062, 2009.

MicroRNAs: Novel regulators in the hallmarks of human cancer

MicroRNAs (miRNAs) are small non-coding RNAs of 18-25 nucleotides in length that function as negative regulators. miRNAs post-transcriptionally regulate gene expression by either inhibiting mRNA translation or inducing mRNA degradation, and participate in a wide variety of physiological and pathological cellular processes. Recent reports have revealed that the deregulation of miRNAs correlates with various human cancers and is involved in the initiation and progression of human cancers. miRNAs can act as oncogenes or tumor suppressors to inhibit the expression of cancer-related target genes and to promote or suppress tumorigenesis in various tissues. Therefore, abnormal miRNA expression can be regarded as a common feature of human cancers, and the identification of miRNAs and their respective targets may provide potential diagnostic and prognostic tumor biomarkers and new therapeutic strategies to treat cancers. In the present review, we discuss the emerging roles of miRNAs in the hallmarks of human cancers.

The multifaceted role of periostin in tumorigenesis

Periostin, also called osteoblast-specific factor 2 (OSF-2), is a member of the fasciclin family and a disulfide-linked cell adhesion protein that has been shown to be expressed preferentially in the periosteum and periodontal ligaments, where it acts as a critical regulator of bone and tooth formation and maintenance. Furthermore, periostin plays an important role in cardiac development. Recent clinical evidence has also revealed that periostin is involved in the development of various tumors, such as breast, lung, colon, pancreatic, and ovarian cancers. Periostin interacts with multiple cell-surface receptors, most notably integrins, and signals mainly via the PI3-K/Akt and other pathways to promote cancer cell survival, epithelial–mesenchymal transition (EMT), invasion, and metastasis. In this review, aspects related to the function of periostin in tumorigenesis are summarized.

Antiproliferation and apoptosis induced by curcumin in human ovarian cancer cells

Curcumin, an active ingredient from the rhizome of the plant, Curcuma longa, has antioxidant, anti‐inflammatory and anti‐cancer activities. It has recently been demonstrated that the chemopreventive activities of curcumin might be due to its ability to inhibit cell growth and induce apoptosis. In the present study, we have investigated the effects of curcumin on growth and apoptosis in the human ovarian cancer cell line Ho‐8910 by MTT assay, fluorescence microscopy, flow cytometry and Western blotting. Our data revealed that curcumin could significantly inhibit the growth and induce apoptosis in Ho‐8910 cells. A decrease in expression of Bcl‐2, Bcl‐XL and pro‐caspase‐3 was observed after exposure to 40 μM curcumin, while the levels of p53 and Bax were increased in the curcumin‐treated cells. These activities may contribute to the anticarcinogenic action of curcumin.

The role of periostin in tissue remodeling across health and disease

Periostin, also termed osteoblast-specific factor 2, is a matricellular protein with known functions in osteology, tissue repair, oncology, cardiovascular and respiratory systems, and in various inflammatory settings. However, most of the research to date has been conducted in divergent and circumscribed areas meaning that the overall understanding of this intriguing molecule remains fragmented. Here, we integrate the available evidence on periostin expression, its normal role in development, and whether it plays a similar function during pathologic repair, regeneration, and disease in order to bring together the different research fields in which periostin investigations are ongoing. In spite of the seemingly disparate roles of periostin in health and disease, tissue remodeling as a response to insult/injury is emerging as a common functional denominator of this matricellular molecule. Periostin is transiently upregulated during cell fate changes, either physiologic or pathologic. Combining observations from various conditions, a common pattern of events can be suggested, including periostin localization during development, insult and injury, epithelial–mesenchymal transition, extracellular matrix restructuring, and remodeling. We propose mesenchymal remodeling as an overarching role for the matricellular protein periostin, across physiology and disease. Periostin may be seen as an important structural mediator, balancing appropriate versus inappropriate tissue adaption in response to insult/injury.

Twist2 contributes to breast cancer progression by promoting an epithelial-mesenchymal transition and cancer stem-like cell self-renewal

The epithelial to mesenchymal transition (EMT) is a highly conserved cellular programme that has an important role in normal embryogenesis and in cancer invasion and metastasis. We report here that Twist2, a tissue-specific basic helix-loop-helix transcription factor, is overexpressed in human breast cancers and lymph node metastases. In mammary epithelial cells and breast cancer cells, ectopic overexpression of Twist2 results in morphological transformation, downregulation of epithelial markers and upregulation of mesenchymal markers. Moreover, Twist2 enhances the cell migration and colony-forming abilities of mammary epithelial cells and breast cancer cells in vitro and promotes tumour growth in vivo. Ectopic expression of Twist2 in mammary epithelial cells and breast cancer cells increases the size and number of their CD44high/CD24low stem-like cell sub-populations, promotes the expression of stem cell markers and enhances the self-renewal capabilities of stem-like cells. In addition, exogenous expression of Twist2 leads to constitutive activation of STAT3 (signal transducer and activator of transcription 3) and downregulation of E-cadherin. Thus, the overexpression of Twist2 may contribute to breast cancer progression by activating the EMT programme and enhancing the self-renewal of cancer stem-like cells.

Genistein induces G2/M cell cycle arrest and apoptosis of human ovarian cancer cells via activation of DNA damage checkpoint pathways

Genistein is a major isoflavonoid in dietary soybean, commonly consumed in Asia. Genistein exerts inhibitory effects on the proliferation of various cancer cells and plays an important role in cancer prevention. However, the molecular and cellular mechanisms of genistein on human ovarian cancer cells are still little known. We show that exposure of human ovarian cancer HO‐8910 cells to genistein induces DNA damage, and triggers G2/M phase arrest and apoptosis. Furthermore, we also found that checkpoint proteins ATM and ATR are phosphorylated and activated in the cells treated with genistein. It is also shown that genistein increases the phosphorylation and activation of Chk1 and Chk2, which results in the phosphorylation and inactivation of phosphatases Cdc25C and Cdc25A, and thereby the phosphorylation and inactivation of Cdc2 which arrests cells in G2/M phase. Moreover, genistein enhances the phosphorylation and activation of p53, while decreases the ratio of Bcl‐2/Bax and Bcl‐xL/Bax and the level of phosphorylated Akt, which result in cells undergoing apoptosis. These results demonstrate that genistein‐activated ATM‐Chk2‐Cdc25 and ATR‐Chk1‐Cdc25 DNA damage checkpoint pathways can arrest ovarian cancer cells in G2/M phase, and induce apoptosis while the cellular DNA damage is too serious to be repaired. Thus, the antiproliferative, DNA damage‐inducing and pro‐apoptotic activities of genistein are probably responsible for its genotoxic effects on human ovarian cancer HO‐8910 cells.

Curcumin induces human HT-29 colon adenocarcinoma cell apoptosis by activating p53 and regulating apoptosis-related protein expression

Curcumin, a major yellow pigment and active component of turmeric, has multiple anti-cancer properties. However, its molecular targets and mechanisms of action on human colon adenocarcinoma cells are unknown. In the present study, we examined the effects of curcumin on the proliferation of human colon adenocarcinoma HT-29 cells by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide method and confirmed the curcumin-induced apoptosis by morphology and DNA ladder formation. At the same time, p53, phospho-p53 (Ser15), and other apoptosis-related proteins such as Bax, Bcl-2, Bcl-xL, pro-caspase-3, and pro-caspase-9 were determined by Western blot analysis. The colon adenocarcinoma cells were treated with curcumin (0-75 microM) for 0-24 h. We observed that p53 was highly expressed in HT-29 cells and curcumin could up-regulate the serine phosphorylation of p53 in a time- and concentration-dependent manner. An increase in expression of the pro-apoptotic factor Bax and a decrease in expression of the anti-apoptotic factor Bcl-2 were also observed in a time-dependent manner after exposure of 50 microM curcumin, while the expression of the anti-apoptotic factor Bcl-xL was unchanged. Curcumin could also down-regulate the expression of pro-caspase-3 and pro-caspase-9 in a time-dependent manner. These data suggest a possible underlying molecular mechanism whereby curcumin could induce the apoptosis signaling pathway in human HT-29 colon adenocarcinoma cells by p53 activation and by the regulation of apoptosis-related proteins. This property of curcumin suggests that it could have a possible therapeutic potential in colon adenocarcinoma patients.