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The molecular and cellular impact of wave interactions on the aggressiveness of PC-3 cells

Weeks, Hoi Ping 2014. The molecular and cellular impact of wave interactions on the aggressiveness of PC-3 cells. PhD Thesis, Cardiff University.
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Abstract

The metastatic spread of cancer cells to distant sites in the body accounts for the majority of cancer-related death and significantly decreases patient survival. Whilst cell migration is a physiologically important process, when uncontrolled, it can be a contributing factor to the metastatic phenotype. Actin polymerisation enables the dynamic restructuring of the cytoskeleton which is fundamental to cell migration and is stimulated by the Arp (actin-related protein) 2/3 protein complex which in turn is activated by members of the WAVE (WASP Verprolin homologous protein) family. WAVE1 and 3 expression was targeted separately in the PC-3 cell line utilising ribozyme transgene transfection. In vitro experiments revealed a reduction in cell growth and invasion following WAVE1 or 3 knockdown in PC-3 cells. These experiments were also repeated with small molecule inhibitors targeting the Arp2/3 complex, ROCK and N-WASP independently. This inhibitor work implicates Arp2/3 as a facilitator of cell proliferation through which WAVE regulates. Inhibition of Arp2/3, ROCK or N-WASP in WAVE1 knockdown cells increased cell invasion which may be attributed to the regulatory role of WAVE3 on MMP activity. Co-localisation of WAVE1 and 3 with ARP2 and ROCK-I was observed in PC-3 cells whilst this affect was abolished with WAVE1 or 3 knockdown. Furthermore, WAVE3 and WAVE1 knockdown affected ARP2 and ROCK-II tyrosine phosphorylation, respectively. These results suggest WAVE1 and 3 proteins are involved in several metastatic traits that characterise PC-3 cells. Furthermore, the contribution of WAVE in the networks that influence these traits may also involve association with Arp2/3 complex, ROCK-I and –II and N-WASP. Additionally, it sheds light on the similarities between these two related proteins and also highlights their subtle distinctions in PC-3 cells. The data outlined here provides justification to futher explore WAVE1 and 3 as potential contributors of prostate cancer progression.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Funders: Desna Robert Jones Charity
Date of First Compliant Deposit: 30 March 2016
Last Modified: 21 Oct 2016 05:13
URI: http://orca-mwe.cf.ac.uk/id/eprint/70578

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