Phosphoproteomics of Retinoblastoma: A Pilot Study Identifies Aberrant Kinases.

Retinoblastoma is a malignant tumour of the retina which most often occurs in children. Earlier studies on retinoblastoma have concentrated on the identification of key players in the disease and have not provided information on activated/inhibited signalling pathways. The dysregulation of protein phosphorylation in cancer provides clues about the affected signalling cascades in cancer. Phosphoproteomics is an ideal tool for the study of phosphorylation changes in proteins. Hence, global phosphoproteomics of retinoblastoma (RB) was carried out to identify signalling events associated with this cancer. Over 350 proteins showed differential phosphorylation in RB compared to control retina. Our study identified stress response proteins to be hyperphosphorylated in RB which included H2A histone family member X (H2AFX) and sirtuin 1. In particular, Ser140 of H2AFX also known as gamma-H2AX was found to be hyperphosphorylated in retinoblastoma, which indicated the activation of DNA damage response pathways. We also observed the activation of anti-apoptosis in retinoblastoma compared to control. These observations showed the activation of survival pathways in retinoblastoma. The identification of hyperphosphorylated protein kinases including Bromodomain containing 4 (BRD4), Lysine deficient protein kinase 1 (WNK1), and Cyclin-dependent kinase 1 (CDK1) in RB opens new avenues for the treatment of RB. These kinases can be considered as probable therapeutic targets for RB, as small-molecule inhibitors for some of these kinases are already in clinical trials for the treatment other cancers.

TIF-IA: An oncogenic target of pre-ribosomal RNA synthesis.

Cancer cells devote the majority of their energy consumption to ribosome biogenesis, and pre-ribosomal RNA transcription accounts for 30-50% of all transcriptional activity. This aberrantly elevated biological activity is an attractive target for cancer therapeutic intervention if approaches can be developed to circumvent the development of side effects in normal cells. TIF-IA is a transcription factor that connects RNA polymerase I with the UBF/SL-1 complex to initiate the transcription of pre-ribosomal RNA. Its function is conserved in eukaryotes from yeast to mammals, and its activity is promoted by the phosphorylation of various oncogenic kinases in cancer cells. The depletion of TIF-IA induces cell death in lung cancer cells and mouse embryonic fibroblasts but not in several other normal tissue types evaluated in knock-out studies. Furthermore, the nuclear accumulation of TIF-IA under UTP down-regulated conditions requires the activity of LKB1 kinase, and LKB1-inactivated cancer cells are susceptible to cell death under such stress conditions. Therefore, TIF-IA may be a unique target to suppress ribosome biogenesis without significantly impacting the survival of normal tissues.

Hyperforin Suppresses Oncogenic Kinases and Induces Apoptosis in Colorectal Cancer Cells.

BACKGROUND/AIM: Signal transducer and activator of transcription 3 (STAT3), Janus Kinase 1 (JAK1), extracellular signal-regulated kinase (ERK), and protein kinase B (AKT) are essential for malignant transformation and progression in colorectal cancer (CRC) and can be considered as targets for therapeutic interventions. Hyperforin, an active constituent from Hypericum perforatum, has been reported to inhibit inflammation. However, whether hyperforin may suppress CRC progression via inactivation of JAK/STAT3, ERK or AKT signaling remains unclear. MATERIALS AND METHODS: Human CRC cells were used to identify the treatment efficacy of hyperforin and its underlying mechanisms of action by MTT, flow cytometry, wound healing, and western blotting assays. RESULTS: Hyperforin not only induced cytotoxicity, extrinsic/intrinsic apoptosis signaling, but also suppressed the invasion/migration ability of CRC. The phosphorylation of STAT3, JAK1, ERK and AKT was found to be decreased by hyperforin. CONCLUSION: Hyperforin inactivates multiple oncogenic kinases and induces apoptosis signaling in CRC cells.

Oncogenic kinases and perturbations in protein synthesis machinery and energetics in neoplasia.

Notwithstanding that metabolic perturbations and dysregulated protein synthesis are salient features of cancer, the mechanism underlying coordination of cellular energy balance with mRNA translation (which is the most energy consuming process in the cell) is poorly understood. In this review, we focus on recently emerging insights in the molecular underpinnings of the cross-talk between oncogenic kinases, translational apparatus and cellular energy metabolism. In particular, we focus on the central signaling nodes that regulate these processes (e.g. the mechanistic/mammalian target of rapamycin MTOR) and the potential implications of these findings on improving the anti-neoplastic efficacy of oncogenic kinase inhibitors.

Translation of cancer immunotherapy from the bench to the bedside.

The tremendous success of immune checkpoint blockades has revolutionized cancer management. Our increased understanding of the cell types that compose the tumor microenvironment (TME), including those of the innate and adaptive immune system, has helped to shape additional immune modulatory strategies in cancer care. Pre-clinical and clinical investigations targeting novel checkpoint interactions and key pathways that regulate cancer immunity continue to increase rapidly. Various combinatorial drug regimens are being tested in attempt to achieve durable response and survival rates of patients with cancer. This review provides an overview of specific components of the TME, an introduction to novel immune checkpoints, followed by a survey of present day and future combination immune modulatory therapies. The idea that the immune system can recognize and destroy tumor cells was first described in the cancer immunosurveillance hypothesis of Burnet and Thomas. However, early experimental evidence failed to support the concept. It was not until the late 1990s when seminal papers clearly showed the existence of cancer immunosurveillance, leading to the cancer immunoediting hypothesis. In this century, progress in the understanding of negative regulators of the immune response led to the discovery that inhibition of these regulators in patients with cancer could lead to dramatic and durable remissions. Drs. Tasuku Honjo and James P. Allison were awarded the Nobel Prize in 2018 for their pioneering work in this field. We now see rapid advances in cancer immunology and emerging effective therapies revolutionizing cancer care across tumor types in the clinic, while pre-clinical research is moving from a focus on the malignant cells themselves to dissect the highly heterogenic and complex multi-cellular tumor microenvironment (TME).