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Jacob S.,National Health Research Institute | Nayak S.,National Health Research Institute | Kakar R.,National Health Research Institute | Chaudhari U.K.,National Health Research Institute | And 6 more authors.
Cancer Biology and Therapy | Year: 2016

Telomerase activation is one of the key mechanisms that allow cells to bypass replicative senescence. Telomerase activity is primarily regulated at the level of transcription of its catalytic unit- hTERT. Prostate cancer (PCa), akin to other cancers, is characterized by high telomerase activity. Existing data suggest that hTERT expression and telomerase activity are positively regulated by androgenic stimuli in androgen-dependent prostate cancer (ADPC) cells. A part of the present study reaffirmed this by demonstrating a decline in the hTERT expression and telomerase activity on “loss of AR” in ADPC cells. The study further addressed 2 unresolved queries, i) whether AR-mediated signaling is of any relevance to hTERT expression in castration-resistant prostate cancer (CRPC) and ii) whether this signaling involves EGR1. Our data suggest that AR-mediated signaling negatively regulates hTERT expression in CRPC cells. Incidental support for the possibility of EGR1 being a regulator of hTERT expression in PCa was provided by i) immunolocalization of hTERT and EGR1 proteins in the same cell type (secretory epithelium) of PCa and BPH tissues; ii) significantly (p< 0.001) higher levels of both these proteins in CRPC (PC3 and DU145), compared with ADPC (LNCaP) cells. A direct evidence for the role of EGR1 in hTERT expression was evident by a significant (p<0.0001) decrease in the hTERT transcript levels in the EGR1-silenced CRPC cells. Further, “gain of AR” led to a significant reduction in the levels of hTERT and EGR1 in CRPC cells. However, restoration of EGR1 levels prevented the decline in the hTERT transcript levels in these cells. Taken together, our data indicate that AR regulates the expression of EGR1, which in turn acts as a positive regulator of hTERT expression in CRPC cells. Thus, AR exerts an inhibitory effect on hTERT expression and telomerase activity by modulating EGR1 levels in CRPC cells. © 2016 National Research In Reproductive Health, Indian Council Of Medical Research. Source

Chaudhary A.K.,National Institute of Immunohaematology NIIH | Pandya S.,Haematopathology Laboratory | Ghosh K.,National Institute of Immunohaematology NIIH | Nadkarni A.,National Institute of Immunohaematology NIIH
Mutation Research - Reviews in Mutation Research | Year: 2013

Matrix metalloproteinase (MMP) comprises a family of zinc-dependent endopeptidases that degrade various components of the extracellular matrix (ECM) and basement membrane. MMPs are involved in solid and hematological malignancy through modification of cell growth, activation of cancer cells and modulation of immune functions. Several polymorphisms of different MMPs such as MMP-1 (-1607 1G/2G), MMP-2 (-1306 C/T), MMP-3 (-1171 5A/6A) & MMP-9 (-1562 C/T) and their expression levels have been well documented in different types of solid cancer. These polymorphic variations were found to be associated with angiogenesis, cancer progression, invasion and metastasis. There is paucity of data available in the field of hematological malignancies. Hence the field of matrix biology of hematological malignancies is an area of active exploration. A number of MMP inhibitors (MMPIs) have been developed for the cancer treatment. The most extensively studied classes of MMP inhibitors include Batimastat, Marismastat, Salimatat, Prinomastat and Tanomastat. However, their efficacy and action have not been confirmed and more data is required. The application of one or more selective targeted MMPIs in combination with conventional anti-leukemic treatment may represent a positive approach in combat against hematopoietic malignancies. Balance of MMPs and TIMPs is altered in different malignancies and biochemical pathways. These alternations will add another dimension in the matrix biology of both solid tumor and leukemia. MMP and TIMP singly and in combination are increasingly being recognized as an important player in basic cellular biology. Exploration and exploitation of MMP and TIMP balance in various malignant and nonmalignant lesions is going to be one of the most interesting facets of future use of this system for human health care. © 2013 Elsevier B.V. Source

Chaudhary A.K.,Allahabad University | Chaudhary A.K.,MOTI | Chaudhary A.K.,National Institute of Immunohaematology | Pandya S.,MOTI | And 3 more authors.
Head and Neck Oncology | Year: 2013

A human papilloma virus (HPV) is well established as heterogeneous virus family and important in human carcinogenesis. It not only causes the vast majority of cervical cancers, but also plays an important role in anogenital as well as oral cancers. Aim of the present study was to detect the HPV 16 and 18 by type specific PCR and multiplex-PCR and also asses their expression by immunohistochemistry (IHC). We analyzed the paraffin embedded tissue sections of 208 and 222 OSMF and OSCC patients respectively. Out of 208 OSMF, 25.96% individuals showed positivity for HR-HPV 16 URR infection and 1.92% for HR-HPV18. In 222 OSCC cases, 32.43% were positive for HR-HPV 16 URR infection and 12% for HPV 18 E6. 1.44% of OSMF samples were positive for co-infection with both HPV 16 URR and 18 E6 infections in late stages of the disease and 3.6% samples were positive for HPV 16 URR and 18 infections coinfection with OSCC cases. IHC analysis showed 12.2% extensive positive expression of HPV 16 URR in case of OSMF. While in case of OSCC, 19.7% cases showed extensive positive expression. In case of higher grade in malignant lesions, immunostaining showed significant (p<0.021) association of HPV 16 URR in OSCC cases. This study concluded that multiplex PCR (MPX-PCR) could be helpful for quick screening of HR-HPVs and it is highly convenient, simple and cost-effective tool for large scale multi-institutional study for developing countries. Source

Shukla P.,National Institute of Immunohaematology NIIH | Ghosh K.,National Institute of Immunohaematology NIIH | Vundinti B.R.,National Institute of Immunohaematology NIIH
HUGO Journal | Year: 2012

Fanconi Anemia (FA) is a rare disorder with incidence of 1in 350,000 births. It is characterized by progressive bone marrow failure leading to death of many patients in their childhood while development of cancer at later stages of life in some. The treatment of FA is still a medical challenge. Current treatments of FA include androgen administration, hematopoietic growth factors administration and hematopoietic stem cell transplantation (HSCT). Clinical gene therapy trials are still ongoing. The partial success of current therapies has renewed interest in the search for new treatments. Generation of patient-specific induced pluripotent stem (iPS) has shown promising results for cell and gene based therapy. Small molecule interventions have been observed to delay tumor onset in FA. Tumors deficient in FA pathway can be treated by profiling of DNA repair pathway through synthetic lethality mechanism. Targeting toll-like receptor 8 (TLR8) dependent TNFα overexpression is yet another upcoming therapeutic approach to treat FA patients. In conclusion, in the present scenario of treatments available for FA, a proper algorithm of treatment decisions must be followed for better management of FA patients and to ensure their increased survival. Innovative therapeutic approaches that can prevent both anemia and cancer should be developed for more effective treatment of FA. © 2012 Shukla et al; licensee Springer. Source

Shukla P.,National Institute of Immunohaematology NIIH | Solanki A.,National Institute of Immunohaematology NIIH | Ghosh K.,National Institute of Immunohaematology NIIH | Vundinti B.R.,National Institute of Immunohaematology NIIH
European Journal of Haematology | Year: 2013

Interstrand cross-links (ICLs) are extremely toxic DNA lesions that prevent DNA double-helix separation due to the irreversible covalent linkage binding of some agents on DNA strands. Agents that induce these ICLs are thus widely used as chemotherapeutic drugs but may also lead to tumor growth. Fanconi anemia (FA) is a rare genetic disorder that leads to ICL sensitivity. This review provides update on current understanding of the role of FA proteins in repairing ICLs at various stages of cell cycle. We also discuss link between DNA cross-link genotoxicity caused by aldehydes in FA pathway. Besides this, we summarize various ICL agents that act as drugs to treat different types of tumors and highlight strategies for modulating ICL sensitivity for therapeutic interventions that may be helpful in controlling cancer and life-threatening disease, FA. © 2013 John Wiley & Sons A/S. Source

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