Examination of the role of sphingosine kinase 2 in a murine model of systemic lupus erythematosus.

Systemic lupus erythematosus is an autoimmune disease characterized by overproduction of type 1 IFN that causes multiple organ dysfunctions. Plasmacytoid dendritic cells (pDCs) that secrete large amounts of IFN have recently been implicated in the initiation of the disease in preclinical mouse models. Sphingosine-1-phosphate, a bioactive sphingolipid metabolite, is produced by 2 highly conserved isoenzymes, sphingosine kinase (SphK) 1 and SphK2, and regulates diverse processes important for immune responses and autoimmunity. However, not much is known about the role of SphK2 in autoimmune disorders. In this work, we examined the role of SphK2 in pDC development and activation and in the pristane-induced lupus model in mice that mimics the hallmarks of the human disease. Increases in pDC-specific markers were observed in peripheral blood of SphK2 knockout mice. In agreement, the absence of SphK2 increased the differentiation of FMS-like tyrosine kinase 3 ligand dendritic cells as well as expression of endosomal TLRs, TLR7 and TLR9, that modulate production of IFN. Surprisingly, however, SphK2 deficiency did not affect the initiation or progression of pristane-induced lupus. Moreover, although absence of SphK2 increased pDC frequency in pristane-induced lupus, there were no major changes in their activation status. Additionally, SphK2 expression was unaltered in lupus patients. Taken together, our results suggest that SphK2 may play a role in dendritic cell development. Yet, because its deletion had no effect on the clinical lupus parameters in this preclinical model, inhibitors of SphK2 might not be useful for treatment of this devastating disease.-Mohammed, S., Vineetha, N. S., James, S., Aparna, J. S., Lankadasari, M. B., Allegood, J. C., Li, Q.-Z., Spiegel, S., Harikumar, K. B. Examination of the role of sphingosine kinase 2 in a murine model of systemic lupus erythematosus.

TAMing pancreatic cancer: combat with a double edged sword.

Among all the deadly cancers, pancreatic cancer ranks seventh in mortality. The absence of any grave symptoms coupled with the unavailability of early prognostic and diagnostic markers make the disease incurable in most of the cases. This leads to a late diagnosis, where the disease would have aggravated and thus, incurable. Only around 20% of the cases present the early disease diagnosis. Surgical resection is the prime option available for curative local disease but in the case of advanced cancer, chemotherapy is the standard treatment modality although the patients end up with drug resistance and severe side effects. Desmoplasia plays a very important role in chemoresistance associated with pancreatic cancer and consists of a thick scar tissue around the tumor comprised of different cell populations. The interplay between this heterogenous population in the tumor microenvironment results in sustained tumor growth and metastasis. Accumulating evidences expose the crucial role played by the tumor-associated macrophages in pancreatic cancer and this review briefly presents the origin from their parent lineage and the importance in maintaining tumor hallmarks. Finally we have tried to address their role in imparting chemoresistance and the therapeutic interventions leading to reduced tumor burden.

Enhanced expression of histone chaperone APLF associate with breast cancer.

DNA damage-specific histone chaperone Aprataxin PNK-like factor (APLF) regulates mesenchymal-to-epithelial transition (MET) during cellular reprogramming. We investigated the role of APLF in epithelial-to-mesenchymal transition (EMT) linked to breast cancer invasiveness and metastasis. Here, we show that a significant manifestation of APLF is present in tumor sections of patients with invasive ductal carcinoma when compared to their normal adjacent tissues. APLF was significantly induced in triple negative breast cancer (TNBC) cells, MDAMB-231, in comparison to invasive MCF7 or normal MCF10A breast cells and supported by studies on invasive breast carcinoma in The Cancer Genome Atlas (TCGA). Functionally, APLF downregulation inhibited proliferative capacity, altered cell cycle behavior, induced apoptosis and impaired DNA repair ability of MDAMB-231 cells. Reduction in APLF level impeded invasive, migratory, tumorigenic and metastatic potential of TNBC cells with loss in expression of genes associated with EMT while upregulation of MET-specific gene E-cadherin (CDH1). So, here we provided novel evidence for enrichment of APLF in breast tumors, which could regulate metastasis-associated EMT in invasive breast cancer. We anticipate that APLF could be exploited as a biomarker for breast tumors and additionally could be targeted in sensitizing cancer cells towards DNA damaging agents.

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.

Cardamonin Attenuates Experimental Colitis and Associated Colorectal Cancer.

Cardamonin is a naturally occurring chalcone, majorly from the Zingiberaceae family, which includes a wide range of spices from India. Herein, we investigated the anti-inflammatory property of cardamonin using different in vitro and in vivo systems. In RAW 264.7 cells, treatment with cardamonin showed a reduced nitrous oxide production without affecting the cell viability and decreased the expression of iNOS, TNF-α, and IL-6, and inhibited NF-kB signaling which emphasizes the role of cardamonin as an anti-inflammatory molecule. In a mouse model of dextran sodium sulfate (DSS)-induced colitis, cardamonin treatment protected the mice from colitis. Subsequently, we evaluated the therapeutic potential of this chalcone in a colitis-associated colon cancer model. We performed microRNA profiling in the different groups and observed that cardamonin modulates miRNA expression, thereby inhibiting tumor formation. Together, our findings indicate that cardamonin has the potential to be considered for future therapy against colorectal cancer.

Acid Ceramidase: A Novel Therapeutic Target in Cancer.

Sphingolipids are important constituents of the eukaryotic cell membrane which govern various signaling pathways related to different aspects of cell survival. Ceramide and Sphingosine are interconvertible sphingolipid metabolites, out of which Ceramide is pro-apoptotic and sphingosine is anti-apoptotic in nature. The conversion of ceramide to sphingosine is mediated by Acid Ceramidase (ASAH1) thus maintaining a rheostat between a tumor suppressor and a tumor promoter. This rheostat is completely altered in many tumors leading to uncontrolled proliferation. This intriguing property of ASAH1 can be used by cancer cells to their advantage, by increasing the expression of the tumor promoter, sphingosine inside cells, thus creating a favorable environment for cancer growth. The different possibilities through which this enzyme serves its role in formation, progression and resistance of different types of cancers will lead to the possibility of making Acid Ceramidase a promising drug target. This review discusses the current understanding of the role of acid ceramidase in cancer progression, metastasis and resistance, strategies to develop novel natural and synthetic inhibitors of ASAH1 and their usefulness in cancer therapy.

Targeting S1PR1/STAT3 loop abrogates desmoplasia and chemosensitizes pancreatic cancer to gemcitabine.

Rationale: Pancreatic cancer is associated with poor prognosis with a 5-year survival rate of less than 6%. Approximately 90% of pancreatic cancer patients harbor somatic mutations in the KRAS gene. Multiple lines of evidence suggest a persistent activation of STAT3 in KRAS-driven oncogenesis contributing to desmoplasia and gemcitabine resistance. Sphingosine 1-phosphate receptor 1 (S1PR1) is an integral component of tumor progression and maintains an activated state of STAT3. FTY720 is an approved drug for multiple sclerosis and acts as a functional antagonist for S1PR1. Here we explored the potential utility of FTY720 to target S1PR1/STAT3 and other major signaling pathways in pancreatic cancer, and sought proof-of-principle for repurposing FTY720 for the treatment of pancreatic cancer. Methods: We examined the activity of FTY720 in the proliferation, apoptosis, and cell cycle assays in human and mouse pancreatic cancer model systems. Further, we studied the efficacy of using a combination of FTY720 and gemcitabine as opposed to individual agents in vitro as well as in vivoResults: Treatment of human and mouse pancreatic cancer cells with FTY720 resulted in inhibition of growth, increased apoptosis, and cell cycle arrest. FTY720 in combination with gemcitabine breached the mitochondrial membrane potential, altered the S1PR1-STAT3 loop, and inhibited epithelial to mesenchymal (EMT) transition. Data from murine models exhibited a marked reduction in the tumor size, increased apoptosis, inhibited NF-κB, S1PR1/STAT3, Shh signaling and desmoplasia, modulated the expression of gemcitabine-metabolizing transport enzymes, and restored the expression of tumor suppressor gene PP2A. Conclusion: Taken together, our results established FTY720 as a propitious molecule, which increases the efficacy of gemcitabine and represents a promising agent in the management of pancreatic cancer.

Cardamonin inhibits colonic neoplasia through modulation of MicroRNA expression.

Colorectal cancer is currently the third leading cause of cancer related deaths. There is considerable interest in using dietary intervention strategies to prevent chronic diseases including cancer. Cardamonin is a spice derived nutraceutical and herein, for the first time we evaluated the therapeutic benefits of cardamonin in Azoxymethane (AOM) induced mouse model of colorectal cancer. Mice were divided into 4 groups of which three groups were given six weekly injections of AOM. One group served as untreated control and remaining groups were treated with either vehicle or Cardamonin starting from the same day or 16 weeks after the first AOM injection. Cardamonin treatment inhibited the tumor incidence, tumor multiplicity, Ki-67 and ß-catenin positive cells. The activation of NF-kB signaling was also abrogated after cardamonin treatment. To elucidate the mechanism of action a global microRNA profiling of colon samples was performed. Computational analysis revealed that there is a differential expression of miRNAs between these groups. Subsequently, we extend our findings to human colorectal cancer and found that cardamonin inhibited the growth, induces cell cycle arrest and apoptosis in human colorectal cancer cell lines. Taken together, our study provides a better understanding of chemopreventive potential of cardamonin in colorectal cancer.