mTORC2 is aberrantly activated in cancer and therefore is considered to be an important therapeutic target. The hedgehog pathway, which is also often hyperactivated, regulates transcription of several genes associated with angiogenesis, metastasis, cellular proliferation and cancer stem cell (CSC) regeneration. However, the contribution of mTORC2 toward hedgehog pathway activity has not been explored yet. Here we have addressed the molecular cross talk between mTORC2 and hedgehog pathway activities in the context of glioblastoma multiforme, a malignant brain tumor using as a model system. We observed that higher mTORC2 activity enhanced the expression of a few hedgehog pathway molecules (Gli1, Gli2 and Ptch1) and amplified its target genes (Cyclin D1, Cyclin D2, Cyclin E, Snail, Slug and VEGF) both in mRNA and protein levels as corroborated by increased metastasis, angiogenesis, cellular proliferation and stem cell regeneration. Inhibition of mTORC2 formation decreased hedgehog pathway activity and attenuated all these above-mentioned events, suggesting their cross talk with each other. Further investigations revealed that mTORC2 inhibited ubiquitination of Gli2 by inactivating GSK3β, and thus it promotes stability to Gli2 and its nuclear translocation. Moreover, enhanced mTORC2 activity led to the increased clonogenic properties and CD133+ cells, indicating its role in CSC regeneration. mTORC2 inhibitor directed the reduction of hedgehog pathway proteins and also reduced CSCs. Thus, our observations support a role for elevated mTORC2 activity in regulating angiogenesis, metastasis, cellular proliferation and CSC regeneration via hedgehog pathway activity. Taken together, it provides a rationale for including the mTOR2 inhibitor as part of the therapeutic regimen for CSCs.
Murraya koenigii is a well-known Indian medicinal herb, and a carbazole alkaloid (mahanine) from this plant causes apoptosis in cancer cells. Here, we investigated how seasonal and geographical variations influence carbazole alkaloids composition and medicinal property of this plant against cancer cells in vitro and in vivo. Leaflets were collected from various places in different seasons for three years. A mahanine-enriched fraction (MEF) was prepared in two steps using ethanol and water. The best plant was selected based on the highest percent of mahanine. MEF prepared from leaflets of nine different locations showed a different concentration of identified markers (mahanine, mahanimbine, and koenimbine) which exhibited differential reduced metabolic activity against ovarian cancer, mahanine being the best. Our systematic study revealed that mahanine content was highest during September–December. Interestingly, MEF from southern part (tropical zone) exhibited 43 ± 2.5% mahanine compared to 2.7 ± 1.3% in northeastern part (subtropical zone) with five folds higher activity against PA1. Moreover, MEF reduced metabolic activity of sixteen cancer cell lines from nine different origins and significantly reduced tumor mass in lung and ovarian cancer xenograft models. Taken together, this is the first report demonstrating the marker’s content in these leaflets is highly dependent on location/season. A positive correlation between biological activity and mahanine concentration was established in MEF. Such a comprehensive study suggests that the selection of location and suitable season for collection of any plant materials with biologically active stable markers in sufficient quantity play a decisive role in determining the fate of their medicinal property.
Leishmania is an obligatory intracellular protozoan parasite responsible for the development of a spectrum of disease manifestation ranging from cutaneous to the more destructive visceral form 1 . Visceral leishmaniasis (VL) is a neglected tropical disease, mainly caused by the species L. donovani, which is prevalent in the Indian subcontinent with 40,000 cases registered each year and 147 million people under the risk 2 . Macrophages are the primary host for the parasite to survive and multiply in the mammalian system. Development of antileishmanial immunity depends on the Th1 type immune response generated by IL-12 secretion by antigen presenting cells (APCs) which in turn induce IFNγ secretion by T cells. This secreted IFNγ further induce macrophages for generation of nitric oxide (NO) and reactive oxygen species (ROS), which are the major antileishmanial defense molecules 3 . Uncoupling protein (UCP) is a mitochondrial membrane transporter which takes part in the regulation of mitochondrial ROS generation in macrophages 4 . Leishmania developed several strategies to dodge the host immune response to the establishment of successful infection in the hostile environment. This parasite induces the expression of negative regulatory protein UCP2 in macrophages as well as utilizes their own cascade of antioxidant enzymes like ascorbate peroxidase (APX), glutathione synthetase, tryparedoxin peroxidase for the suppression of ROS generation thereby neutralizing oxidative stress in host for their survival [5][6][7][8] . Due to unavailability of effective vaccines, treatment solely relies on chemotherapy. Although pentavalent antimonials were the mainstream therapy for past 70 years, a large percentage of patients are resistant to this drug. Currently, amphotericin B (conventional deoxycholate or liposomal formulations) has emerged as the first line of treatment. Miltefosine is the only oral drug. However, emerging resistance to miltefosine is particularly worrying. Alongside, most of these synthetic antileishmanial drugs are highly expensive and suffer from various side effects, long treatment regimen and acute toxicity, thus pose a real challenge for the management and elimination
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