Asmita Das

Synergistic Signals for Natural Cytotoxicity Are Required to Overcome Inhibition by c-Cbl Ubiquitin Ligase

Natural killer (NK) cell cytotoxicity toward target cells depends on synergistic coactivation by NK cell receptors such as NKG2D and 2B4. How synergy occurs is not known. Synergistic phosphorylation of phospholipase PLC-gamma2, Ca(2+) mobilization, and degranulation triggered by NKG2D and 2B4 coengagement were blocked by Vav1 siRNA knockdown, but enhanced by knockdown of c-Cbl. c-Cbl inhibited Vav1-dependent signals, given that c-Cbl knockdown did not rescue the Vav1 defect. Moreover, c-Cbl knockdown and Vav1 overexpression each circumvented the necessity for synergy because NKG2D or 2B4 alone became sufficient for activation. Thus, synergy requires not strict complementation but, rather, strong Vav1 signals to overcome inhibition by c-Cbl. Inhibition of NK cell cytotoxicity by CD94-NKG2A binding to HLA-E on target cells was dominant over synergistic activation, even after c-Cbl knockdown. Therefore, NK cell activation by synergizing receptors is regulated at the level of Vav1 by a hierarchy of inhibitory mechanisms.

Role of interleukin-6 in cancer progression and therapeutic resistance

In the last several decades, the number of people dying from cancer-related deaths has not reduced significantly despite phenomenal advances in the technologies related to diagnosis and therapeutic modalities. The principal cause behind limitations in the curability of this disease is the reducing sensitivity of the cancer cells towards conventional anticancer therapeutic modalities, particularly in advance stages of the disease. Amongst several reasons, certain secretory factors released by the tumour cells into the microenvironment have been found to confer resistance towards chemo- and radiotherapy, besides promoting growth. Interleukin-6 (IL-6), one of the major cytokines in the tumour microenvironment, is an important factor which is found at high concentrations and known to be deregulated in cancer. Its overexpression has been reported in almost all types of tumours. The strong association between inflammation and cancer is reflected by the high IL-6 levels in the tumour microenvironment, where it promotes tumorigenesis by regulating all hallmarks of cancer and multiple signalling pathways, including apoptosis, survival, proliferation, angiogenesis, invasiveness and metastasis, and, most importantly, the metabolism. Moreover, IL-6 protects the cancer cells from therapy-induced DNA damage, oxidative stress and apoptosis by facilitating the repair and induction of countersignalling (antioxidant and anti-apoptotic/pro-survival) pathways. Therefore, blocking IL-6 or inhibiting its associated signalling independently or in combination with conventional anticancer therapies could be a potential therapeutic strategy for the treatment of cancers with IL-6-dominated signalling.

Radiation-induced autophagy: mechanisms and consequences

ABSTRACT Autophagy is an evolutionary conserved, indispensable, lysosome-mediated degradation process, which helps in maintaining homeostasis during various cellular traumas. During stress, a context-dependent role of autophagy has been observed which drives the cell towards survival or death depending upon the type, time, and extent of the damage. The process of autophagy is stimulated during various cellular insults, e.g. oxidative stress, endoplasmic reticulum stress, imbalances in calcium homeostasis, and altered mitochondrial potential. Ionizing radiation causes ROS-dependent as well as ROS-independent damage in cells that involve macromolecular (mainly DNA) damage, as well as ER stress induction, both capable of inducing autophagy. This review summarizes the current understanding on the roles of oxidative stress, ER stress, DNA damage, altered mitochondrial potential, and calcium imbalance in radiation-induced autophagy as well as the merits and limitations of targeting autophagy as an approach for radioprotection and radiosensitization.

Use of ligand-based pharmacophore modeling and docking approach to find novel acetylcholinesterase inhibitors for treating Alzheimer's

Alzheimers disease is a neurological disorder in which the patient suffers from memory loss and impaired cognitive abilities. Though the main cause of the disease is not yet known, depletion of neurotransmitter at synaptic junctions, accumulation of insoluble beta amyloid plaques and neurofibrillary tangles are the main pathologies associated with it. The FDA approved drugs for alzheimers belong to the category of acetylcholinesterase inhibitors. But most of the drugs have been observed to be associated with adverse side effects. In this study, we have developed a pharmacophore (responsible for interaction with acetylcholinesterase active site) based on the already existing drugs and drug candidates. This pharmacophore was used to search for novel AChE inhibitors with altogether different chemical scaffold using high throughput virtual screening and docking studies. Finally, we have reported two compounds, OPA and OMT, which possess high affinity for catalytic site of AChE enzyme and thus, can be considered as potential AChE inhibitors for the symptomatic treatment of Alzheimers.

Role of BRCA Mutations in the Modulation of Response to Platinum Therapy

Recent years have seen cancer emerge as one of the leading cause of mortality worldwide with breast cancer being the second most common cause of death among women. Individuals harboring BRCA mutations are at a higher risk of developing breast and/or ovarian cancers. This risk is much greater in the presence of germline mutations. BRCA1 and BRCA2 play crucial role in the DNA damage response and repair pathway, a function that is critical in preserving the integrity of the genome. Mutations that interfere with normal cellular function of BRCA not only lead to onset and progression of cancer but also modulate therapy outcome of treatment with platinum drugs. In this review, we discuss the structural and functional impact of some of the prevalent BRCA mutations in breast and ovarian cancers and their role in platinum therapy response. Understanding the response of platinum drugs in the context of BRCA mutations may contribute toward developing better therapeutics that can improve survival and quality of life of patients.

IL-2 mediates NK cell proliferation but not hyperactivity

Natural killer cells play a major role in innate immunity against tumor and virus-infected cells. NK cells express activating and inhibitory receptors to regulate their function. It has been established that modulation in the NK cell receptor profile results in altered function of NK cell against target cells. Here, we study the effect of IL-2 stimulation on NK cell inhibitory receptors Ly49A, Ly49C, and activating receptor Ly49D in C57BL/6 mice. It was observed that there was significant increase in expression of Ly49A but no change in expression of Ly49C and Ly49D on IL-2 stimulation. We further noticed that although IL-2 stimulation increased the NK cell population and expression of activation marker NK1.1 but IL-2 stimulation does not cause hyper-responsiveness in NK cells, as there was no increase in MIP-1α and IFN-γ production in IL-2 stimulated NK cells as compared to unstimulated controls. These findings provide a framework to understand the effect of IL-2 stimulation on cognate and non-cognate receptor ligand interactions and suggest stratagies for immunotherapies in conjunction with IL-2 combinatorial therapies.

Detection of Multidrug-Resistant Fungal Infections in Cancer Patients

Candida albicans is a commensal organism but in immuno-compromisedo individuals like those suffering from cancer, HIV infection, patients undergoing transplantation therapy, burn victims etc., various immunosuppressive drugs are given which impairs the immune system of the individual and in these cases it causes opportunistic infection of C. albicans. Candida infection has become a serious problem nowadays due to the development of resistance against various antifungal drugs which are administered during the treatment. The cells of Candida acquire multiple drug resistance (MDR) which may be either due to change in membrane permeability, mutations of ERG genes, defect in ergosterol biosynthetic pathway, mutations in the drug efflux pump proteins, alterations in membrane lipids and lipid-protein interactions, resulting in change in membrane permeability and Candida becomes resistant to azoles as well as other drugs which are given to patients who are immuno-compromised like those who are suffering from cancer. This chapter highlights the importance of MDR Candida infection in cancer patients thus necessitating better diagnostic methods and regular monitoring of opportunistic fungal infections.