miR-433 overexpression attenuates the spindle assembly checkpoint response to paclitaxel

Fiona Furlong, Maria Prencipe, Aloysius McGoldrick, Paul McGettigan, D Carney, Emma Doyle, Elaine W Kay, Amanda McCann

Research output: Contribution to conferenceAbstract

Abstract

Paclitaxel is a microtubule inhibitory chemotherapeutic drug that is increasingly used for the treatment of solid tumours. In vitro studies have demonstrated that attenuating the spindle assemble checkpoint (SAC) alters the post-mitotic responses to paclitaxel. Furthermore, the aberrant expression of a number of the SAC proteins, MAD2, BUBR1, and Aurora A kinase, are associated with poor patient prognosis. We have identified a microRNA, miR-433, that regulates the expression of MAD2. Overexpression of miR-433 in Hela cells induced downregulation of MAD2 mRNA and protein expression. We have also shown that Hela cells overexpressing miR-433 and treated with paclitaxel are no longer capable of cyclin B stabilisation, and thus have lost the ability to activate the SAC in response to paclitaxel. In addition, cell viability assays showed that Hela cells overexpressing miR-433 and treated with paclitaxel have an attenuated response to paclitaxel compared with microRNA scrambled controls. We have characterised the levels of miR-433, MAD2 gene expression and MAD2 protein levels in a cohort of ovarian cancer cell lines. Cell viability assays on this cohort revealed that responsiveness to paclitaxel is associated with high MAD2 protein expression and lower miR-433 expression. We hypothesise that the expression of miR-433 when deregulated in cancer leads to altered MAD2 expression and a compromised SAC, a key feature underlying drug resistance to paclitaxel. In a pilot study of paired human breast tumour and normal breast tissue samples we have shown that expression levels of miR-433 are elevated in cancer tissue. Targeting this microRNA in cancer may improve the efficacy of paclitaxel in treating breast cancer and ovarian cancer.
Original languageEnglish
Pages35
DOIs
Publication statusPublished - 2010
EventConference on Breast Cancer Research - London, United Kingdom
Duration: 18 May 2010 → …

Conference

ConferenceConference on Breast Cancer Research
CountryUnited Kingdom
CityLondon
Period18/05/2010 → …

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    Furlong, F., Prencipe, M., McGoldrick, A., McGettigan, P., Carney, D., Doyle, E., W Kay, E., & McCann, A. (2010). miR-433 overexpression attenuates the spindle assembly checkpoint response to paclitaxel. 35. Abstract from Conference on Breast Cancer Research, London, United Kingdom. https://doi.org/10.1186/bcr2532