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Kholia, Sharadkumar Rajnikant (2014) The role of PADs in the biogenesis of prostate cancer microvesicles which play a dysfunctional role on DC biology and the therapeutic potential of skeletal muscle microvesicles on prostate cancer cells. Doctoral thesis, London Metropolitan University.
Microvesicles (MVs) are small, plasma membrane derived vesicles that are shed constitutively or upon activation from both normal and malignant cells. Apart from physiological roles, MVs have also been implicated to play a role in various pathologies particularly cancer. Aspects of MV biogenesis and function have therefore become emerging targets for further research and cancer therapy. In light with the current research this thesis reports for the first time a novel function of peptidylarginine deiminase (PAD) isozymes (elevated in cancer cells) in the biogenesis of MVs. It was reported here that during the stimulation of cancer cells to microvesiculate, PAD expression and deimination of cytoskeletal-actins is increased. Inhibiting the enzyme with pan-PAD inhibitor chloramidine, abrogated the deimination of cytoskeletal actins as well as reduced the release of MVs. Furthermore, combining chloramidine with anticancer drug methotrexate increased the cytotoxic effect of the drug synergistically on different types of cancer cells. It is also reported for the first time the cytotoxic and anti-proliferative effects of myocyte MVs on prostate cancer cells. Treating prostate cancer cells with MVs from myocytes reduced proliferation and induced apoptosis. Furthermore mass spectrometry analysis of the MVs revealed a candidate protein gelsolin that has been reported to exhibit anti-tumourigenic properties.
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