http://www.molecular-cancer.com The most accessed research articles published by Molecular Cancer 2012-04-26T00:00:00Z About 80% of pancreatic cancer patients have glucose intolerance or frank diabetes. This observation has led to the following two hypotheses: i. pancreatic cancer causes the associated diabetes and ii. the conditions associated with diabetes promote the development of pancreatic cancer. Evidence supporting both hypotheses has been accumulated in previous studies. This article reviews these studies, especially those that have been conducted recently. http://www.molecular-cancer.com/content/2/1/4 Feng Wang Margery Herrington Jorgen Larsson Johan Permert Molecular Cancer 2003, null:4 2003-01-06T00:00:00Z doi:10.1186/1476-4598-2-4 /content/figures/1476-4598-2-4-toc.gif Molecular Cancer 1476-4598 ${item.volume} 4 2003-01-06T00:00:00Z XML Background: MicroRNAs (miRNAs) have been suggested to play a vital role in tumor initiation and progression by negatively regulating oncogenes and tumor suppressors. Quite recently, studies have identified some miRNAs operating to promote or suppress tumor invasion or metastasis via regulating metastasis-related genes, providing potential therapeutic targets on anti-metastasis strategy. Metastasis-associated in colon cancer-1 (MACC1) has been newly identified to express highly in colorectal cancer (CRC) and promote tumor metastasis through transactivating metastasis-inducing HGF/MET signaling pathway. In this study, we investigated whether miRNA 143 is involved in the regulation of MACC1 and thus plays a functional role in CRC. Results: Using both in silico prediction and western blot assay, we found the previously reported tumor suppressive miR-143 targeted MACC1 in CRC. The direct interaction between them was confirmed by 3' UTR luciferase reporter gene. In concordance with the inhibitory effects induced by siRNA mediated knockdown of MACC1, restoration of miR-143 by mimics in SW620 cells significantly attenuated cell growth, migration and invasion. It is notable that combined treatment of miR-143 mimics and MACC1 siRNA induced synergistic inhibitory effects compared to either miR-143 mimics or MACC1 siRNA treatment alone. Conversely, reduction of miR-143 by inhibitors in SW480 cells apparently stimulated these phenotypes. Furthermore, we observed that miR-143 level was inversely correlated with MACC1 mRNA expression in CRC tissues. Conclusions: Our findings newly described miR-143/MACC1 link and provided a potential mechanism for MACC1 dysregulation and contribution to CRC cell invasion. It may help to estimate the therapeutic utility of miR-143 in CRC. http://www.molecular-cancer.com/content/11/1/23 Yu Zhang Zhongqiu Wang Min Chen Liang Peng Xinying Wang Qunying Ma Fengli Ma Bo Jiang Molecular Cancer 2012, null:23 2012-04-25T00:00:00Z doi:10.1186/1476-4598-11-23 /content/figures/1476-4598-11-23-toc.gif Molecular Cancer 1476-4598 ${item.volume} 23 2012-04-25T00:00:00Z XML Curcumin (diferuloylmethane) is a polyphenol derived from the Curcuma longa plant, commonly known as turmeric. Curcumin has been used extensively in Ayurvedic medicine for centuries, as it is nontoxic and has a variety of therapeutic properties including anti-oxidant, analgesic, anti-inflammatory and antiseptic activity. More recently curcumin has been found to possess anti-cancer activities via its effect on a variety of biological pathways involved in mutagenesis, oncogene expression, cell cycle regulation, apoptosis, tumorigenesis and metastasis. Curcumin has shown anti-proliferative effect in multiple cancers, and is an inhibitor of the transcription factor NF-κB and downstream gene products (including c-myc, Bcl-2, COX-2, NOS, Cyclin D1, TNF-α, interleukins and MMP-9). In addition, curcumin affects a variety of growth factor receptors and cell adhesion molecules involved in tumor growth, angiogenesis and metastasis. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and treatment protocols include disfiguring surgery, platinum-based chemotherapy and radiation, all of which may result in tremendous patient morbidity. As a result, there is significant interest in developing adjuvant chemotherapies to augment currently available treatment protocols, which may allow decreased side effects and toxicity without compromising therapeutic efficacy. Curcumin is one such potential candidate, and this review presents an overview of the current in vitro and in vivo data supporting its therapeutic activity in head and neck cancer as well as some of the challenges concerning its development as an adjuvant chemotherapeutic agent. http://www.molecular-cancer.com/content/10/1/12 Reason Wilken Mysore Veena Marilene Wang Eri Srivatsan Molecular Cancer 2011, null:12 2011-02-07T00:00:00Z doi:10.1186/1476-4598-10-12 /content/figures/1476-4598-10-12-toc.gif Molecular Cancer 1476-4598 ${item.volume} 12 2011-02-07T00:00:00Z XML Long non-coding RNAs (lncRNAs) are emerging as new players in the cancer paradigm demonstrating potential roles in both oncogenic and tumor suppressive pathways. These novel genes are frequently aberrantly expressed in a variety of human cancers, however the biological functions of the vast majority remain unknown. Recently, evidence has begun to accumulate describing the molecular mechanisms by which these RNA species function, providing insight into the functional roles they may play in tumorigenesis. In this review, we highlight the emerging functional role of lncRNAs in human cancer. http://www.molecular-cancer.com/content/10/1/38 Ewan Gibb Carolyn Brown Wan Lam Molecular Cancer 2011, null:38 2011-04-13T00:00:00Z doi:10.1186/1476-4598-10-38 /content/figures/1476-4598-10-38-toc.gif Molecular Cancer 1476-4598 ${item.volume} 38 2011-04-13T00:00:00Z XML Background: Platinum compounds such as cisplatin and carboplatin are DNA crosslinking agents widelyused for cancer chemotherapy. However, the effectiveness of platinum compounds is oftentempered by the acquisition of cellular drug resistance. Until now, no pharmacologicalapproach has successfully overcome cisplatin resistance in cancer treatment. Since theFanconi anemia (FA) pathway is a DNA damage response pathway required for cellularresistance to DNA interstrand crosslinking agents, identification of small molecules thatinhibit the FA pathway may reveal classes of chemicals that sensitize cancer cells to cisplatin. Results: Through a cell-based screening assay of over 16,000 chemicals, we identified 26 smallmolecules that inhibit ionizing radiation and cisplatin-induced FANCD2 foci formation, amarker of FA pathway activity, in multiple human cell lines. Most of these small moleculesalso compromised ionizing radiation-induced RAD51 foci formation and homologousrecombination repair, indicating that they are not selective toward the regulation of FANCD2.These compounds include known inhibitors of the proteasome, cathepsin B, lysosome,CHK1, HSP90, CDK and PKC, and several uncharacterized chemicals including a novelproteasome inhibitor (Chembridge compound 5929407).Isobologram analyses demonstrated that half of the identified molecules sensitized ovariancancer cells to cisplatin. Among them, 9 demonstrated increased efficiency toward FApathway-proficient, cisplatin-resistant ovarian cancer cells. Six small molecules, includingbortezomib (proteasome inhibitor), CA-074-Me (cathepsin B inhibitor) and 17-AAG (HSP90inhibitor), synergized with cisplatin specifically in FA-proficient ovarian cancer cells(2008 + FANCF), but not in FA-deficient isogenic cells (2008). In addition, geldanamycin(HSP90 inhibitor) and two CHK1 inhibitors (UCN-01 and SB218078) exhibited asignificantly stronger synergism with cisplatin in FA-proficient cells when compared to FAdeficientcells, suggesting a contribution of their FA pathway inhibitory activity to cisplatinsensitization. Conclusion: Our findings suggest that, despite their lack of specificity, pharmaceutical inhibition of theFA pathway by bortezomib, CA-074-Me, CHK1 inhibitors or HSP90 inhibitors may be apromising strategy to sensitize cisplatin-resistant, FA pathway-proficient tumor cells tocisplatin. In addition, we identified four new small molecules which synergize with cisplatin.Further development of their analogs and evaluation of their combination with cisplatin maylead to the development of efficient cancer treatments. http://www.molecular-cancer.com/content/11/1/26 Celine Jacquemont Julian Simon Alan D'Andrea Toshiyasu Taniguchi Molecular Cancer 2012, null:26 2012-04-26T00:00:00Z doi:10.1186/1476-4598-11-26 /content/figures/1476-4598-11-26-toc.gif Molecular Cancer 1476-4598 ${item.volume} 26 2012-04-26T00:00:00Z PDF Background: TAK733 is a novel allosteric, non-ATP-binding, inhibitor of the BRAF substrates MEK-1/2. Methods: The growth inhibitory effects of TAK733 were assessed in a panel of 27 cutaneous and five uveal melanoma cell lines genotyped for driver oncogenic mutations. Flow cytometry, Western blots and metabolic tracer uptake assays were used to characterize the changes induced by exposure to TAK733. Results: Fourteen cutaneous melanoma cell lines with different driver mutations were sensitive to the antiproliferative effects of TAK733, with a higher proportion of BRAFV600E mutant cell lines being highly sensitive with IC50s below 1 nM. The five uveal melanoma cell lines had GNAQ or GNA11 mutations and were either moderately or highly sensitive to TAK733. The tested cell lines wild type for NRAS, BRAF, GNAQ and GNA11 driver mutations were moderately to highly resistant to TAK733. TAK733 led to a decrease in pERK and G1 arrest in most of these melanoma cell lines regardless of their origin, driver oncogenic mutations and in vitro sensitivity to TAK733. MEK inhibition resulted in increase in pMEK more prominently in NRASQ61L mutant and GNAQ mutant cell lines than in BRAFV600E mutant cell lines. Uptake of the metabolic tracers FDG and FLT was inhibited by TAK733 in a manner that closely paralleled the in vitro sensitivity assays. Conclusions: The MEK inhibitor TAK733 has antitumor properties in melanoma cell lines with different oncogenic mutations and these effects could be detectable by differential metabolic tracer uptake. http://www.molecular-cancer.com/content/11/1/22 Erika von Euw Mohammad Atefi Narsis Attar Connie Chu Sybil Zachariah Barry Burgess Stephen Mok Charles Ng Deborah Wong Bartosz Chmielowski David Lichter Richard Koya Tara McCannel Elena Izmailova Antoni Ribas Molecular Cancer 2012, null:22 2012-04-19T00:00:00Z doi:10.1186/1476-4598-11-22 /content/figures/1476-4598-11-22-toc.gif Molecular Cancer 1476-4598 ${item.volume} 22 2012-04-19T00:00:00Z PDF Cyclin D1 is an important regulator of cell cycle progression and can function as a transcriptionl co-regulator. The overexpression of cyclin D1 has been linked to the development and progression of cancer. Deregulated cyclin D1 degradation appears to be responsible for the increased levels of cyclin D1 in several cancers. Recent findings have identified novel mechanisms involved in the regulation of cyclin D1 stability. A number of therapeutic agents have been shown to induce cyclin D1 degradation. The therapeutic ablation of cyclin D1 may be useful for the prevention and treatment of cancer. In this review, current knowledge on the regulation of cyclin D1 degradation is discussed. Novel insights into cyclin D1 degradation are also discussed in the context of ablative therapy. A number of unresolved questions regarding the regulation of cellular cyclin D1 levels are also addressed. http://www.molecular-cancer.com/content/6/1/24 John Alao Molecular Cancer 2007, null:24 2007-04-02T00:00:00Z doi:10.1186/1476-4598-6-24 /content/figures/1476-4598-6-24-toc.gif Molecular Cancer 1476-4598 ${item.volume} 24 2007-04-02T00:00:00Z XML Mitochondria play important roles in cellular energy metabolism, free radical generation, and apoptosis. Defects in mitochondrial function have long been suspected to contribute to the development and progression of cancer. In this review article, we aim to provide a brief summary of our current understanding of mitochondrial genetics and biology, review the mtDNA alterations reported in various types of cancer, and offer some perspective as to the emergence of mtDNA mutations, their functional consequences in cancer development, and therapeutic implications. http://www.molecular-cancer.com/content/1/1/9 Jennifer Carew Peng Huang Molecular Cancer 2002, null:9 2002-12-09T00:00:00Z doi:10.1186/1476-4598-1-9 /content/figures/1476-4598-1-9-toc.gif Molecular Cancer 1476-4598 ${item.volume} 9 2002-12-09T00:00:00Z XML Background: In normal cells proliferation and apoptosis are tightly regulated, whereas in tumor cells the balance is shifted in favor of increased proliferation and reduced apoptosis. Anticancer agents mediate tumor cell death via targeting multiple pathways of programmed cell death. We have reported that the non-pathogenic, tumor suppressive Adeno-Associated Virus Type 2 (AAV2) induces apoptosis in Human Papillomavirus (HPV) positive cervical cancer cells, but not in normal keratinocytes. In the current study, we examined the potential of AAV2 to inhibit proliferation of MCF-7 and MDA-MB-468 (both weakly invasive), as well as MDA-MB-231 (highly invasive) human breast cancer derived cell lines. As controls, we used normal human mammary epithelial cells (nHMECs) isolated from tissue biopsies of patients undergoing breast reduction surgery. Results: AAV2 infected MCF-7 line underwent caspase-independent, and MDA-MB-468 and MDA-MB-231 cell lines underwent caspase-dependent apoptosis. Death of MDA-MB-468 cells was marked by caspase-9 activation, whereas death of MDA-MB-231 cells was marked by activation of both caspase-8 and caspase-9, and resembled a mixture of apoptotic and necrotic cell death. Cellular demise was correlated with the ability of AAV2 to productively infect and differentially express AAV2 non-structural proteins: Rep78, Rep68 and Rep40, dependent on the cell line. Cell death in the MCF-7 and MDA-MB-231 lines coincided with increased S phase entry, whereas the MDA-MB-468 cells increasingly entered into G2. AAV2 infection led to decreased cell viability which correlated with increased expression of proliferation markers c-Myc and Ki-67. In contrast, nHMECs that were infected with AAV2 failed to establish productive infection or undergo apoptosis. Conclusion: AAV2 regulated enrichment of cell cycle check-point functions in G1/S, S and G2 phases could create a favorable environment for Rep protein expression. Inherent Rep associated endonuclease activity and AAV2 genomic hair-pin ends have the potential to induce a cellular DNA damage response, which could act in tandem with c-Myc regulated/sensitized apoptosis induction. In contrast, failure of AAV2 to productively infect nHMECs could be clinically advantageous. Identifying the molecular mechanisms of AAV2 targeted cell cycle regulation of death inducing signals could be harnessed for developing novel therapeutics for weakly invasive as well as aggressive breast cancer types. http://www.molecular-cancer.com/content/10/1/97 Samina Alam Brian Bowser Michael Conway Mohd Israr Apurva Tandon Craig Meyers Molecular Cancer 2011, null:97 2011-08-09T00:00:00Z doi:10.1186/1476-4598-10-97 /content/figures/1476-4598-10-97-toc.gif Molecular Cancer 1476-4598 ${item.volume} 97 2011-08-09T00:00:00Z XML Background: Metastatic melanoma is a lethal skin cancer and its incidence is rising every year. Itrepresents a challenge for oncologist, as the current treatment options are non-curative in themajority of cases; therefore, the effort to find and/or develop novel compounds is mandatory.Pemetrexed (Alimta(R), MTA) is a multitarget antifolate that inhibits folate-dependentenzymes: thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotideformyltransferase, required for de novo synthesis of nucleotides for DNA replication. It iscurrently used in the treatment of mesothelioma and non-small cell lung cancer (NSCLC),and has shown clinical activity in other tumors such as breast, colorectal, bladder, cervical,gastric and pancreatic cancer. However, its effect in human melanoma has not been studiedyet. Results: In the current work we studied the effect of MTA on four human melanoma cell lines A375,Hs294T, HT144 and MeWo and in two NSCLC cell lines H1299 and Calu-3. We have foundthat MTA induces DNA damage, S-phase cell cycle arrest, and caspase- dependent and -independent apoptosis. We show that an increment of the intracellular reactive oxygenspecies (ROS) and p53 is required for MTA-induced cytotoxicity by utilizing N-Acetyl-LCysteine(NAC) to blockage of ROS and p53-defective H1299 NSCLC cell line.Pretreatment of melanoma cells with NAC significantly decreased the DNA damage, p53 upregulationand cytotoxic effect of MTA. MTA was able to induce p53 expression leading toup-regulation of p53-dependent genes Mcl-1 and PIDD, followed by a postranscriptionalregulation of Mcl-1 improving apoptosis. Conclusions: We found that MTA induced DNA damage and mitochondrial-mediated apoptosis in humanmelanoma cells in vitro and that the associated apoptosis was both caspase-dependent and -independent and p53-mediated. Our data suggest that MTA may be of therapeutic relevancefor the future treatment of human malignant melanoma. http://www.molecular-cancer.com/content/11/1/25 Aitziber Buqué Jangi Sh Muhialdin Alberto Muñoz Begoña Calvo Sergio Carrera Unai Aresti Aintzane Sancho Itziar Rubio Guillermo López-Vivanco Molecular Cancer 2012, null:25 2012-04-26T00:00:00Z doi:10.1186/1476-4598-11-25 /content/figures/1476-4598-11-25-toc.gif Molecular Cancer 1476-4598 ${item.volume} 25 2012-04-26T00:00:00Z PDF