Cross-talk between AMP-activated protein kinase and the sonic hedgehog pathway in the high-fat diet triggered colorectal cancer.

The major cause of colorectal cancer (CRC) related mortality is due to its metastasis. Signaling pathways play a definite role in the development and progression of CRC. Recent studies demonstrate that the regulation of the sonic hedgehog (Shh) pathway is beneficial in the CRC treatment strategy. Also, 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a well-known regulator of metabolism and inflammation, making it a suitable treatment option for CRC. Consumption of a high-fat diet (HFD) is a significant cause of CRC genesis. Also, the lipids play an indispensable role in aberrant activation of the Shh pathway. This review explains in detail the interconnection between HFD consumption, Shh pathway activation, and the progression of CRC. According to recent studies and literature, AMPK is a potential regulator that can control the complexities of CRC and reduce lipid levels and may directly inhibit shh signalling. The review also suggests the possible risk elements of AMPK activation in CRC due to its context-dependent role. Also, the activation of AMPK in HFD-induced CRC may modulate cancer progression by regulating the Shh pathway and metabolism.

S1PR1 signaling in cancer: A current perspective.

Sphingosine-1-phosphate receptor 1 (S1PR1) is a G-protein coupled receptor for the bioactive lysosphingolipid sphingosine 1-phosphate (S1P). S1PR1 belongs to the sphingosine-1-phosphate receptor subfamily comprising five members (S1PR1-5). It has prominent roles in regulating endothelial cell cytoskeletal structure, cell migration, immunomodulation, vasculogenesis during embryogenesis, T cell egress and Multiple sclerosis. This review is addressing the role of S1PR1 in tumorigenesis and therapeutic opportunities to target S1PR1 in cancer.

Corrigendum: Sphingosine 1-Phosphate: A Novel Target for Lung Disorders.

[This corrects the article DOI: 10.3389/fimmu.2017.00296.].

The Origin and Functions of Exosomes in Cancer.

Exosomes are nanovesicles having a maximum size of 150 nm and is a newly emerging focus in various fields of research. Its role in cargo trafficking along with its differential expression is associated with the disrupted homeostasis and provides an opportunity to defend against different diseases like cancer. Furthermore, exosomes are rich in cargos, which contain proteins and nucleic acids that directly reflect the metabolic state of the cells from which it originates. This review summarizes recent studies on tumor-derived exosomes with an overview about biogenesis, their functions and potential of using as diagnostic and prognostic markers. We also discussed the current challenges and microfluidic-based detection approaches that might improve the detection of exosomes in different settings. More intricate studies of the molecular mechanisms in angiogenesis, pre-metastatic niche formation, and metastasis can give more promising insights and novel strategies in oncotherapeutics.

Targeting oncogenic transcription factors by polyphenols: A novel approach for cancer therapy.

Inflammation is one of the major causative factor of cancer and chronic inflammation is involved in all the major steps of cancer initiation, progression metastasis and drug resistance. The molecular mechanism of inflammation driven cancer is the complex interplay between oncogenic and tumor suppressive transcription factors which include FOXM1, NF-kB, STAT3, Wnt/ß- Catenin, HIF-1α, NRF2, androgen and estrogen receptors. Several products derived from natural sources modulate the expression and activity of multiple transcription factors in various tumor models as evident from studies conducted in cell lines, pre-clinical models and clinical samples. Further combination of these natural products along with currently approved cancer therapies added an additional advantage and they considered as promising targets for prevention and treatment of inflammation and cancer. In this review we discuss the application of multi-targeting natural products by analyzing the literature and future directions for their plausible applications in drug discovery.

Sphingosine 1-Phosphate: A Novel Target for Lung Disorders.

Sphingosine 1-phosphate (S1P) is involved in a wide range of cellular processes, which include proliferation, apoptosis, lymphocyte egress, endothelial barrier function, angiogenesis, and inflammation. S1P is produced by two isoenzymes, namely, sphingosine kinase 1 and 2 (SphK1 and 2) and once produced, S1P can act both in an autocrine and paracrine manner. S1P can be dephosphorylated back to sphingosine by two phosphatases (SGPP 1 and 2) or can be irreversibly cleaved by S1P lyase. S1P has a diverse range of functions, which is mediated in a receptor dependent, through G-protein coupled receptors (S1PR1-5) or receptor independent manner, through intracellular targets such as HDACs and TRAF2. The involvement of S1P signaling has been confirmed in various disease conditions including lung diseases. The SphK inhibitors and S1PR modulators are currently under clinical trials for different pathophysiological conditions. There is a significant effort in targeting various components of S1P signaling for several diseases. This review focuses on the ways in which S1P signaling can be therapeutically targeted in lung disorders.

Proapoptotic and antitumor activities of the HMG-CoA reductase inhibitor, lovastatin, against Dalton's lymphoma ascites tumor in mice.

BACKGROUND: Diet rich in fat have a clear effect on the tumor incidence in humans. Increased level of lipid peroxidation were found in colon, liver, breast and kidney carcinogenesis. Although the beneficial effects of statins for cardiovascular diseases are well established, their importance in the area of cancer therapeutics has recently gained recognition. Many studies of lovastatin in in vitro systems and experimental animals have been reported as an effective antitumor agent. However, phase I/II clinical trials in cancer patients demonstrated a minor to non-significant responses. Hence more studies in different tumor models using doses corresponding to that used to reduce lipid in human are required to support the antitumor activity. METHODS: The antitumor activity was evaluated using Daltons' Lymphoma Ascites (DLA) cell line-induced ascites tumor model in mice. Proapoptotic activity was evaluated in DLA cell line induced ascites animals after the treatment of lovastatin. Apoptosis was analyzed morphologically by staining with Giemsa and biochemically by observing the laddering of DNA in agarose gel electrophoresis. In vitro cytotoxic activity of lovastatin was studied by trypan blue dye exclusion method. Lipid peroxidation inhibiting activity was demonstrated in Fe2+-ascorbate induced rat whole liver homogenate. RESULTS: Lovastatin dose dependently inhibited the ascites tumor growth at 4 and 16 mg/kg body wt (p.o). The percentage increase in life span (%ILS) in the 16 mg/kg treated group was 61.8% (P<0.01). Single dose of lovastatin (16 mg/kg body wt, p.o) was also effective to accelerate the apoptosis in the ascites tumor bearing mice that was evident from the multiple fragmentation of DNA in gel electrophoresis. Further the morphological analysis of DLA cells aspirated from the lovastatin treated animals showed a significant (P<0.01) increase of apoptotic cells (15.5+/-3%) than the control animals (6.5+/-1%). Concentration of lovastatin required for the 50% of the cytotoxicity was 37+/-5 microg/ml. Lovastatin at its low concentrations were effective to inhibit lipid peroxidation. CONCLUSIONS: The antitumor activity of lovastatin against the ascites tumor is due to its proapoptotic and cytotoxic activities. Lovastatin at low concentrations inhibited Fe2+ induced lipid peroxidation in in vitro system. The proapoptotic and lipid peroxidation inhibiting activities of the lipid lowering drug lovastatin may further suggest its possible therapeutic use as a cancer chemopreventive agent.