MACC1-Dependent Antitumor Effect of Curcumin in Colorectal Cancer.

Metastasis is the main reason for the high mortality rate of colorectal cancer (CRC) patients. Despite the whole improvement in the field of cancer medicine, the treatment options for the patient in the late stages are very restricted. Our previous studies have elucidated metastasis-associated in colon cancer 1 (MACC1) as a direct link to metastasis formation. Therefore, we have aimed to inhibit its expression by using natural products, which are recently the center of most studies due to their low side effects and good tolerability. In this study, we have investigated the effect of one of the promising natural products, curcumin, on MACC1 expression and MACC1-induced tumor-promoting pathways. Curcumin reduced the MACC1 expression, restricted the MACC1-induced proliferation, and was able to reduce the MACC1-induced cell motility as one of the crucial steps for the distant dissemination of the tumor. We further showed the MACC1-dependent effect of curcumin on clonogenicity and wound healing. This study is, to our knowledge, the first identification of the effect of curcumin on the restriction of cancer motility, proliferation, and colony-forming ability by using MACC1 as a target.

Insulin signaling represents a gating mechanism between different memory phases in Drosophila larvae.

The ability to learn new skills and to store them as memory entities is one of the most impressive features of higher evolved organisms. However, not all memories are created equal; some are short-lived forms, and some are longer lasting. Formation of the latter is energetically costly and by the reason of restricted availability of food or fluctuations in energy expanses, efficient metabolic homeostasis modulating different needs like survival, growth, reproduction, or investment in longer lasting memories is crucial. Whilst equipped with cellular and molecular pre-requisites for formation of a protein synthesis dependent long-term memory (LTM), its existence in the larval stage of Drosophila remains elusive. Considering it from the viewpoint that larval brain structures are completely rebuilt during metamorphosis, and that this process depends completely on accumulated energy stores formed during the larval stage, investing in LTM represents an unnecessary expenditure. However, as an alternative, Drosophila larvae are equipped with the capacity to form a protein synthesis independent so-called larval anaesthesia resistant memory (lARM), which is consolidated in terms of being insensitive to cold-shock treatments. Motivated by the fact that LTM formation causes an increase in energy uptake in Drosophila adults, we tested the idea of whether an energy surplus can induce the formation of LTM in the larval stage. Suprisingly, increasing the metabolic state by feeding Drosophila larvae the disaccharide sucrose directly before aversive olfactory conditioning led to the formation of a protein synthesis dependent longer lasting memory. Moreover, formation of this memory component is accompanied by the suppression of lARM. We ascertained that insulin receptors (InRs) expressed in the mushroom body Kenyon cells suppresses the formation of lARM and induces the formation of a protein synthesis dependent longer lasting memory in Drosophila larvae. Given the numerical simplicity of the larval nervous system this work offers a unique prospect to study the impact of insulin signaling on the formation of protein synthesis dependent memories on a molecular level.

Saffron Crudes and Compounds Restrict MACC1-Dependent Cell Proliferation and Migration of Colorectal Cancer Cells.

The high mortality rate of colorectal cancer (CRC) patients is directly associated with metastatic dissemination. However, therapeutic options specifically for metastasis are still limited. We previously identified Metastasis-Associated in Colon Cancer 1 (MACC1) as a major causal metastasis-inducing gene. Numerous studies confirmed its value as a biomarker for metastasis risk. We investigated the inhibitory impact of saffron on MACC1-induced cancer cell growth and motility. Saffron crudes restricted the proliferation and migration of MACC1-expressing CRC cells in a concentration- and MACC1-dependent manner. Saffron delays cell cycle progression at G2/M-phase and does not induce apoptosis. Rescue experiments showed that these effects are reversible. Analysis of active saffron compounds elucidated that crocin was the main compound that reproduced total saffron crudes effects. We showed the interaction of MACC1 with the cancer stem cell (CSC) marker DCLK1, which contributes to metastasis formation in different tumor entities. Saffron extracts reduced DCLK1 with crocin being responsible for this reduction. Saffron's anti-proliferative and anti-migratory effects in MACC1-expressing cells are mediated by crocin through DCLK1 down-regulation. This research is the first identification of saffron-based compounds restricting cancer cell proliferation and motility progression via the novel target MACC1.

Small Ones to Fight a Big Problem-Intervention of Cancer Metastasis by Small Molecules.

Metastasis represents the most lethal attribute of cancer and critically limits successful therapies in many tumor entities. The clinical need is defined by the fact that all cancer patients, who have or who will develop distant metastasis, will experience shorter survival. Thus, the ultimate goal in cancer therapy is the restriction of solid cancer metastasis by novel molecularly targeted small molecule based therapies. Biomarkers identifying cancer patients at high risk for metastasis and simultaneously acting as key drivers for metastasis are extremely desired. Clinical interventions targeting these key molecules will result in high efficiency in metastasis intervention. In result of this, personalized tailored interventions for restriction and prevention of cancer progression and metastasis will improve patient survival. This review defines crucial biological steps of the metastatic cascade, such as cell dissemination, migration and invasion as well as the action of metastasis suppressors. Targeting these biological steps with tailored therapeutic strategies of intervention or even prevention of metastasis using a wide range of small molecules will be discussed.

Anatomy and behavioral function of serotonin receptors in Drosophila melanogaster larvae.

The biogenic amine serotonin (5-HT) is an important neuroactive molecule in the central nervous system of the majority of animal phyla. 5-HT binds to specific G protein-coupled and ligand-gated ion receptors to regulate particular aspects of animal behavior. In Drosophila, as in many other insects this includes the regulation of locomotion and feeding. Due to its genetic amenability and neuronal simplicity the Drosophila larva has turned into a useful model for studying the anatomical and molecular basis of chemosensory behaviors. This is particularly true for the olfactory system, which is mostly described down to the synaptic level over the first three orders of neuronal information processing. Here we focus on the 5-HT receptor system of the Drosophila larva. In a bipartite approach consisting of anatomical and behavioral experiments we describe the distribution and the implications of individual 5-HT receptors on naïve and acquired chemosensory behaviors. Our data suggest that 5-HT1A, 5-HT1B, and 5-HT7 are dispensable for larval naïve olfactory and gustatory choice behaviors as well as for appetitive and aversive associative olfactory learning and memory. In contrast, we show that 5-HT/5-HT2A signaling throughout development, but not as an acute neuronal function, affects associative olfactory learning and memory using high salt concentration as a negative unconditioned stimulus. These findings describe for the first time an involvement of 5-HT signaling in learning and memory in Drosophila larvae. In the longer run these results may uncover developmental, 5-HT dependent principles related to reinforcement processing possibly shared with adult Drosophila and other insects.