Targeting Phosphatases and Kinases: How to Checkmate Cancer

Metastatic disease represents the major cause of death in oncologic patients worldwide. Accumulating evidence have highlighted the relevance of a small population of cancer cells, named cancer stem cells (CSCs), in the resistance to therapies, as well as cancer recurrence and metastasis. Standard anti-cancer treatments are not always conclusively curative, posing an urgent need to discover new targets for an effective therapy. Kinases and phosphatases are implicated in many cellular processes, such as proliferation, differentiation and oncogenic transformation. These proteins are crucial regulators of intracellular signaling pathways mediating multiple cellular activities. Therefore, alterations in kinases and phosphatases functionality is a hallmark of cancer. Notwithstanding the role of kinases and phosphatases in cancer has been widely investigated, their aberrant activation in the compartment of CSCs is nowadays being explored as new potential Achille’s heel to strike. Here, we provide a comprehensive overview of the major protein kinases and phosphatases pathways by which CSCs can evade normal physiological constraints on survival, growth, and invasion. Moreover, we discuss the potential of inhibitors of these proteins in counteracting CSCs expansion during cancer development and progression

The Werner Syndrome Protein Suppresses Telomeric Instability Caused by Chromium (VI) Induced DNA Replication Stress

Telomeres protect the chromosome ends and consist of guanine-rich repeats coated by specialized proteins. Critically short telomeres are associated with disease, aging and cancer. Defects in telomere replication can lead to telomere loss, which can be prevented by telomerase-mediated telomere elongation or activities of the Werner syndrome helicase/exonuclease protein (WRN). Both telomerase and WRN attenuate cytotoxicity induced by the environmental carcinogen hexavalent chromium (Cr(VI)), which promotes replication stress and DNA polymerase arrest. However, it is not known whether Cr(VI)-induced replication stress impacts telomere integrity. Here we report that Cr(VI) exposure of human fibroblasts induced telomeric damage as indicated by phosphorylated H2AX (γH2AX) at telomeric foci. The induced γH2AX foci occurred in S-phase cells, which is indicative of replication fork stalling or collapse. Telomere fluorescence in situ hybridization (FISH) of metaphase chromosomes revealed that Cr(VI) exposure induced an increase in telomere loss and sister chromatid fusions that were rescued by telomerase activity. Human cells depleted for WRN protein exhibited a delayed reduction in telomeric and non-telomeric damage, indicated by γH2AX foci, during recovery from Cr(VI) exposure, consistent with WRN roles in repairing damaged replication forks. Telomere FISH of chromosome spreads revealed that WRN protects against Cr(VI)-induced telomere loss and downstream chromosome fusions, but does not prevent chromosome fusions that retain telomere sequence at the fusion point. Our studies indicate that environmentally induced replication stress leads to telomere loss and aberrations that are suppressed by telomerase-mediated telomere elongation or WRN functions in replication fork restoration

Effect of Duration and Amplitude of Direct Current When Lidocaine is Delivered by Iontophoresis

Dosage for the galvanic stimulation for iontophoresis varies. Clinicians manipulate the duration or the amplitude of the current, but it is not known which is more effective. We compared the anesthetic effect of lidocaine HCL (2%) by manipulating the current parameters on 21 healthy volunteers (age: 21.2 ± 4.2, height 170.7 ± 10.2 cm, mass 82.1 ± 19.2 kg). Three conditions were administered in a random order using a Phoresor II® with 2 mL, 2% lidocaine HCL in an iontophoresis electrode. (1) HASD (40 mA*min): High amplitude (4 mA), short duration (10 min); (2) LALD (40 mA.min): Low amplitude (2 mA), long duration (20 min); (3) Sham condition (0 mA, 20 min). Semmes-Weinstein monofilament (SWM) scores were taken pre and post intervention to measure sensation changes. Two-way ANOVA with repeated measures was used to compare sensation. Both iontophoresis treatments: LALD (4.2 ± 0.32 mm) and HASD (4.2 ± 0.52 mm) significantly increased SWM scores, indicating an increase in anesthesia, compared to the sham condition (3.6 ± 0.06 mm) p \u3c 0.05. Neither LALD nor HASD was more effective and there was no difference in anesthesia with the sham. Lidocaine delivered via iontophoresis reduces cutaneous sensation. However, there was no benefit in either a HASD or LALD treatment

Nobiletin and xanthohumol sensitize colorectal cancer stem cells to standard chemotherapy

Colorectal cancer (CRC) mortality is mainly caused by patient refractoriness to common anti-cancer therapies and consequent metastasis formation. Besides, the notorious toxic side effects of chemotherapy are a concurrent obstacle to be tackled. Thus, new treatment approaches are needed to effectively improve patient outcomes. Compelling evidence demonstrated that cancer stem cells (CSCs) are responsible for treatment failure and relapse. New natural treatment approaches showed capabilities to selectively target the CSC subpopulation by rendering them targetable by standard cytotoxic compounds. Herein we show the anti-cancer properties of the polymethoxyflavones and prenylflavonoids extracted from Citrus sinensis and Humulus lupulus, respectively. The natural biofunctional fractions, singularly and in combination, reduced the cell viability of CRC stem cells (CR-CSCs) and synergized with 5-fluorouracil and oxaliplatin (FOX) chemotherapy. These phenomena were accompanied by a reduced S and G2/M phase of the cell cycle and upregulation of cell death-related genes. Notably, both phytoextracts in combination with FOX thwarted stemness features in CR-CSCs as demonstrated by the impaired clonogenic potential and decreased Wnt pathway activation. Extracts lowered the expression of CD44v6 and affected the expansion of metastatic CR-CSCs in patients refractory to chemotherapy. Together, this study highlights the importance of polymethoxyflavones and prenylflavonoids as natural remedies to aid oncological therapies

Inhibition of the Pim1 oncogene results in diminished visual function

Our objective was to profile genetic pathways whose differential expression correlates with maturation of visual function in zebrafish. Bioinformatic analysis of transcriptomic data revealed Jak-Stat signalling as the pathway most enriched in the eye, as visual function develops. Real-time PCR, western blotting, immunohistochemistry and in situ hybridization data confirm that multiple Jak-Stat pathway genes are up-regulated in the zebrafish eye between 3-5 days post-fertilisation, times associated with significant maturation of vision. One of the most up-regulated Jak-Stat genes is the proto-oncogene Pim1 kinase, previously associated with haematological malignancies and cancer. Loss of function experiments using Pim1 morpholinos or Pim1 inhibitors result in significant diminishment of visual behaviour and function. In summary, we have identified that enhanced expression of Jak-Stat pathway genes correlates with maturation of visual function and that the Pim1 oncogene is required for normal visual function.Jun Yin, Lisa Shine, Francis Raycroft, Sudhakar Deeti, Alison Reynolds, Kristin M. Ackerman, Antonino Glaviano, Sean O'Farrell, Olivia O'Leary, Claire Kilty, Ciaran Kennedy, Sarah McLoughlin, Megan Rice, Eileen Russell, Desmond G. Higgins, David R. Hyde, Breandan N. Kenned

PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer

Abstract The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed.

The metal ion theory of ageing: dietary target hazard quotients beyond radicals

Numerous theories of ageing exist and many are interconnected when viewed through a modern integrative biology perspective. Diet provides a link to a large number of the theories that prevail at the molecular levels. In particular, metal ions form key elements of the radical theory along with having established roles in several age-related neurodegenerative disorders. Lifetime exposure to metals has been linked to ageing by contributions to oxidative stress and neurodegenerative disorders. As many foodstuffs contain high levels and diverse profiles of metals, their cumulative effect on ageing warrants investigation. The cumulative level of concern from environmental exposure can be expressed as a dimensionless index of target hazard quotient (THQ) or for known carcinogens, the target cancer risk (TR). This paper posits that a quantifiable relationship exists between ageing and level of concern resulting from cumulated metal exposure; and that this relationship can be used to develop an ageing-related index of concern from chronic metal ion exposure. As individual differences may facilitate or moderate this cumulated exposure, the potential influence on ageing or on the development of neurodegenerative disorders should be included into the model