Metastasis is the most lethal step in the progression of cancer, and the five-year survival rate for metastatic lung cancer patients is less than 5%. An essential step for metastasis is resistance to anoikis, a cell death program physiologically induced by detachment of cells from the extracellular matrix. Heat shock transcription factor 1 (HSF1) is the master regulator of heat shock proteins (HSP), and HSF1 and HSP promote cell survival and protein homeostasis during stress. In cancer, HSF1 dynamically controls a network of genes beyond HSP, is a mediator of malignant transformation, and promotes metastasis. HSF1 has been linked to anchorage-independent growth, but whether it exerts its effect by supporting anoikis resistance is largely unknown. Using NSCLC cells, we identified HSF1 as a novel supporter of anoikis resistance. Knockdown of HSF1 sensitizes NSCLC cells to anoikis, yet HSF1 expression or activation does not confer anoikis resistance to normal bronchial epithelial cells, suggesting parallel oncogenic pathways may be required to inhibit anoikis. Consistent with the ability of HSF1 to regulate HSP, HSF1 knockdown partially inhibited HSP72, HSP40, and HSP27. However, targeted inhibition of each HSP did not induce anoikis, suggesting the mechanism of HSF1 is unrelated to these HSP. Intriguingly, HSF1 activation markers were increased in response to cell detachment in H460 cells. Except for HSP60 in A549 cells, cell detachment did not induce HSP, further suggesting an alternative mechanism for HSF1. Interestingly, knockdown of HSP60 sensitized A549 cells to anoikis, despite HSF1 knockdown having no effect on HSP60. This work provides novel evidence that HSF1 and HSP60 can promote anchorage independence by supporting anoikis resistance, and may be valuable targets for future efforts to therapeutically suppress metastasis.
|Advisor:||Murphy, Suzanne K.|
|Commitee:||Moore, Catherine, Pape-Zambito, Dana, Peethambaran, Bela|
|School:||University of the Sciences in Philadelphia|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 79/04(E), Dissertation Abstracts International|
|Subjects:||Biology, Molecular biology, Cellular biology|
|Keywords:||Anchorage-independence, Anoikis, HSFI, HSP, Heat shock proteins, Heat shock transcription factor I, Metastasis, NSCLC, Non-small cell lung cancer|
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