We recently demonstrated that Sirt1, a NAD + dependent histone deacetylase, was overexpressed in prostate cancer (PCa) and its inhibition resulted in a significant anti-proliferative response in human PCa cells. Studies have suggested a link between Sirt1 and circadian rhythms, the disruption of which has been linked to cancer. Interestingly, a decreased production of the pineal melatonin has been shown to deregulate the circadian rhythm machinery and increase cancer risk. Further, disruption in melatonin production and circadian rhythmicity has been associated with aging. Here, we challenged our hypothesis that melatonin will impart anti-proliferative response against PCa via inhibiting Sirt1. We demonstrated that melatonin significantly inhibited Sirt1 protein and activity in vitro in multiple human PCa cell lines and melatonin-mediated Sirt1 inhibition was accompanied with a significant decrease in the proliferative potential of PCa cells, but not of normal cells. Forced overexpression of Sirt1 partially rescued the PCa cells from melatonin's anti-proliferative effects, suggesting that Sirt1 is a direct target of melatonin. Employing TRAMP mice, we also demonstrated that oral administration of melatonin, at human achievable doses, significantly inhibited PCa tumorigenesis as shown by decreases in (i) prostate and genitourinary (GU) weight, (ii) serum insulin-like growth factor-1 (IGF-1)/IGF-binding protein-3 (IGFBP3) ratio, (iii) mRNA and protein levels of the proliferation markers (PCNA, Ki-67). This anti-PCa response was accompanied with a significant decrease in Sirt1 in TRAMP prostate. Our data identified melatonin as a novel inhibitor of Sirt1 and suggest that melatonin can inhibit PCa growth via Sirt1 inhibition.

Melanoma, one of the most lethal forms of skin cancer, remains resistant to currently available treatments. Therefore, novel mechanism and target-based approaches are needed for the management of this neoplasm. Polo-like kinase 1 (Plk1) has been shown to be a crucial regulator of mitotic entry, progression and exit. Elevated Plk1 has been associated with aggressiveness of several cancer types as well as with poor disease prognosis. However, the role of Plk1 in melanoma is not well-established. Here, we demonstrate that Plk1 is over-expressed in both clinical tissue specimens and cultured human melanoma cells (WM115, A375 and HS294T) when compared to normal skin tissues and cultured normal melanocytes, respectively. Further, Plk1 gene knockdown via Plk1 specific shRNA or its activity inhibition by a small molecule inhibitor resulted in a significant decrease in the viability and growth of melanoma cells without affecting normal human melanocytes. In addition, Plk1 inhibition resulted in a significant i) decrease in clonogenic survival, ii) multiple mitotic errors, iii) G2/M cell cycle arrest, and iv) apoptosis of melanoma cells. This study suggests Plk1 may have a functional relevance towards melanoma development and/or progression. We suggest that targeting of Plk1 may be a viable approach for the treatment of melanoma.

Mitosis, a critical and highly orchestrated event in the cell cycle, decides how cells divide and transmit genetic information from one cell generation to the next. Errors in the choreography of these events may lead to uncontrolled proliferation, aneuploidy, and genetic instability culminating in cancer development. Considering the central role of phosphorylation in mitotic checkpoints, spindle function, and chromosome segregation, it is not surprising that several mitotic kinases have been implicated in tumorigenesis. Th ese kinases play pivotal roles throughout cellular division. From DNA damage and spindle assembly checkpoints before entering mitosis, to kinetochore and centrosome maturation and separation, to regulating the timing of entrance and exit of mitosis, mitotic kinases are essential for cellular integrity. Th erefore, targeting the mitotic kinases that control the fi delity of chromosome transmission seems to be a promising avenue in the management of cancer. Th is review provides an insight into the mechanism of mitotic signaling, especially the role of critical mitotic kinases. We have also discussed the possibilities of the use of mitotic kinases in crafting novel strategies in cancer management. [Mol Cancer Th er 2007;6(7):1920-31]

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Mitosis, a critical and highly orchestrated event in the cell cycle, decides how cells divide and transmit genetic information from one cell generation to the next. Errors in the choreography of these events may lead to uncontrolled proliferation, aneuploidy, and genetic instability culminating in cancer development. Considering the central role of phosphorylation in mitotic checkpoints, spindle function, and chromosome segregation, it is not surprising that several mitotic kinases have been implicated in tumorigenesis. These kinases play pivotal roles throughout cellular division. From DNA damage and spindle assembly checkpoints before entering mitosis, to kinetochore and centrosome maturation and separation, to regulating the timing of entrance and exit of mitosis, mitotic kinases are essential for cellular integrity. Therefore, targeting the mitotic kinases that control the fidelity of chromosome transmission seems to be a promising avenue in the management of cancer. This review provides an insight into the mechanism of mitotic signaling, especially the role of critical mitotic kinases. We have also discussed the possibilities of the use of mitotic kinases in crafting novel strategies in cancer management. [Mol Cancer Ther 2007;6(7):1920 -31]