Cancer is responsible for one in eight deaths worldwide, with more than twelve million new cases diagnosed yearly. A large percentage of patients die after developing cancer despite aggressive treatment, indicating a need for new approaches to cancer therapy. The push for development of novel diagnostic and therapeutic agents has allowed translational cancer research to flourish. Genomic and proteomic technologies have generated an enormous amount of information critical to expanding our understanding of cancer biology. New research on the differences between normal and malignant cell biology has paved the way for the development of drugs targeted to specific biological molecules, potentially increasing antitumor efficacy while minimizing the toxicity to the patient that is seen with conventional therapeutics. Current targets in include regulators of cell cycle, angiogenesis, apoptosis, DNA repair, and growth factors and their receptors. Collaboration among researchers, clinicians, and pharmaceutical companies is vital to conducting clinical trials to translate laboratory findings into clinically applicable therapeutics. In this review, we discuss current therapeutic approaches and present an introduction to a wide range of topics undergoing investigation in an effort to highlight the importance of translational research in the development of clinically relevant therapeutic strategies.

Tumor hypoxia is a pathophysiologic outcome of disrupted microcirculation with inadequate supply of oxygen, leading to enhanced proliferation, epithelial-mesenchymal transition (EMT), metastasis, and chemo-resistance. Epigenetic changes induced by hypoxia are well documented, and they lead to tumor progression. Recent advances show that DNA demethylation mediated by the Ten-eleven translocation (TET) proteins induces major epigenetic changes and controls key steps of cancer development. TET enzymes serve as 5mC (5-methylcytosine)-specific dioxygenases and cause DNA demethylation. Hypoxia activates the expression of TET1, which also serves as a co-activator of HIF-1α transcriptional regulation to modulate HIF-1α downstream target genes and promote epithelial-mesenchymal transition. As HIF is a negative prognostic factor for tumor progression, hypoxia-activated prodrugs (HAPs) may provide a favorable therapeutic approach to lessen hypoxia-induced malignancy.

As we celebrate the New Year of 2009, we are pleased to announce that the American Journal of Translational Research has been launched with the strong support and enthusiastic participation of the editorial members and fellow investigators from the biomedical research community.

Hec1 and Nuf2, core components of the NDC80 complex, are essential for kinetochore-microtubule attachment and chromosome segregation. It has been shown that both Hec1 and Nuf2 utilize their coiled-coil domains to form a functional dimer; however, details of the consequential significance and structural requirements to form the dimerization interface have yet to be elucidated. Here, we showed that Hec1 required three contiguous heptad repeats from Leu-324 to Leu-352, but not the entire first coiled-coil domain, to ensure overall stability of the NDC80 complex through direct interaction with Nuf2. Substituting the hydrophobic core residues, Leu-331, Val-338, and Ile-345, of Hec1 with alanine completely eliminated Nuf2 binding and blocked mitotic progression. Moreover, unlike most coiled-coil proteins, where the buried positions are composed of hydrophobic residues, Hec1 possessed an unusual distribution of glutamic acid residues, Glu-334, Glu-341, and Glu-348, buried within the interior dimerization interface, which complement with three Nuf2 lysine residues: Lys-227, Lys-234, and Lys-241. Substituting these corresponding residues with alanine diminished the binding affinity between Hec1 and Nuf2, compromised NDC80 complex formation, and adversely affected mitotic progression. Taken together, these findings demonstrated that three buried glutamic acid-lysine pairs, in concert with hydrophobic interactions of core residues, provide the major specificity and stability requirements for Hec1-Nuf2 dimerization and NDC80 complex formation.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadliest cancer worldwide. The primary reasons for this are the lack of early detection methods and targeted therapy. Emerging evidence highlights the metabolic addiction of cancer cells as a potential target to combat PDAC. Oncogenic mutations of KRAS are the most common triggers that drive glucose uptake and utilization via metabolic reprogramming to support PDAC growth. Conversely, high glucose levels in the pancreatic microenvironment trigger genome instability and de novo mutations, including KRAS^G12D, in pancreatic cells through metabolic reprogramming. Here, we review convergent and diverse metabolic networks related to oncogenic KRAS mutations between PDAC initiation and progression, emphasizing the interplay among oncogenic mutations, glucose metabolic reprogramming, and the tumor microenvironment. Recognizing cancer-related glucose metabolism will provide a better strategy to prevent and treat the high risk PDAC population.

Aberrant sugar metabolism is linked to an increased risk of pancreatic cancer. Previously, we found that high glucose induces genome instability and de novo oncogenic KRAS mutation preferentially in pancreatic cells through dysregulation of O-GlcNAcylation. Increasing O-GlcNAcylation by extrinsically supplying N-acetyl-D-glucosamine (GlcNAc) causes genome instability in all kinds of cell types regardless of pancreatic origin. Since many people consume excessive amount of sugar (glucose, fructose, and sucrose) in daily life, whether high sugar consumption directly causes genome instability in animals remains to be elucidated. In this communication, we show that excess sugar in the daily drink increases DNA damage and protein O-GlcNAcylation preferentially in pancreatic tissue but not in other kinds of tissue of mice. The effect of high sugar on the pancreatic tissue may be attributed to the intrinsic ratio of GFAT and PFK activity, a limiting factor that dictates UDP-GlcNAc levels. On the other hand, GlcNAc universally induces DNA damage in all six organs examined. Either inhibiting O-GlcNAcylation or supplementing dNTP pool diminishes the induced DNA damage in these organs, indicating that the mechanism of action is similar to that of high glucose treatment in pancreatic cells. Taken together, these results suggest the potential hazards of high sugar drinks and high glucosamine intake to genomic instability and possibly cancer initiation.

Cancer is a consequence of mutations in genes that control cell proliferation, differentiation and cellular homeostasis. These genes are classified into two categories: oncogenes and tumor suppressor genes. Together, overexpression of oncogenes and loss of tumor suppressors are the dominant driving forces for tumorigenesis. Hence, targeting oncogenes and tumor suppressors hold tremendous therapeutic potential for cancer treatment. In the last decade, the predominant cancer drug discovery strategy has relied on a traditional reductionist approach of dissecting molecular signaling pathways and designing inhibitors for the selected oncogenic targets. Remarkable therapies have been developed using this approach; however, targeting oncogenes is only part of the picture. Our understanding of the importance of tumor suppressors in preventing tumorigenesis has also advanced significantly and provides a new therapeutic window of opportunity. Given that tumor suppressors are frequently mutated, deleted, or silenced with loss-of-function, restoring their normal functions to treat cancer holds tremendous therapeutic potential. With the rapid expansion in our knowledge of cancer over the last several decades, developing effective anticancer regimens against tumor suppressor pathways has never been more promising. In this article, we will review the concept of tumor suppression, and outline the major therapeutic strategies and challenges of targeting tumor suppressor networks for cancer therapeutics.

Breast cancer is the most common cancer and the second leading cause of death in U.S. women. Due to early detection and advanced treatment, the breast cancer death rate has been declining since 1990. However, disease recurrence is still the major obstacle in moving from therapy to truly curative treatments. Recent evidence has indicated that breast cancer recurrence is often caused by a subpopulation of breast cancer cells. This subset of cancer cells, usually referred to as breast cancer stem cells (BCSCs), exhibits stem cell phenotypes. They can self-renew and asymmetrically divide to more differentiated cancer cells. These cells are also highly resistant to conventional therapeutic reagents. Therefore, identifying and characterizing these BCSC subpopulations within the larger population of breast cancer cells is essential for developing new strategies to treat breast cancer and prevent recurrence. In this review article, we discuss the current proposed model for the origin of tumor heterogeneity, summarize the recent findings of cell surface and cytoplasmic markers for BCSC identification, review the regulatory mechanisms by which BCSCs maintain or non-cancer stem cells acquire BCSC characteristics, describe the proposed strategies to eliminate BCSCs, and highlight the current limitations and challenges to translate basic BCSC research to clinical application including establishment of clinical biomarkers and therapeutic treatments specifically targeting BCSCs.

Mammalian mitochondrial mRNA (mt-mRNA) transcripts are polyadenylated at the 3' end with different lengths. The SUV3·PNPase complex and mtPAP have been shown to degrade and polyadenylate mt mRNA, respectively. How these two opposite actions are coordinated to modulate mt-mRNA poly(A) lengths is of interest to pursue. Here, we demonstrated that a fraction of the SUV3·PNPase complex interacts with mitochondrial polyadenylation polymerase (mtPAP) under low mitochondrial matrix inorganic phosphate (Pi) conditions. In vitro binding experiments using purified proteins suggested that SUV3 binds to mtPAP through the N-terminal region around amino acids 100-104, distinctive from the C-terminal region around amino acids 510-514 of SUV3 for PNPase binding. mtPAP does not interact with PNPase directly, and SUV3 served as a bridge capable of simultaneously binding with mtPAP and PNPase. The complex consists of a SUV3 dimer, a mtPAP dimer, and a PNPase trimer, based on the molecular sizing experiments. Mechanistically, SUV3 provides a robust single strand RNA binding domain to enhance the polyadenylation activity of mtPAP. Furthermore, purified SUV3·PNPase·mtPAP complex is capable of lengthening or shortening the RNA poly(A) tail lengths in low or high Pi/ATP ratios, respectively. Consistently, the poly(A) tail lengths of mt-mRNA transcripts can be lengthened or shortened by altering the mitochondrial matrix Pi levels via selective inhibition of the electron transport chain or ATP synthase, respectively. Taken together, these results suggested that SUV3·PNPase·mtPAP form a transient complex to modulate mt-mRNA poly(A) tail lengths in response to cellular energy changes.