Abstract
Spermine/spermidine N1-acetyltransferase (SSAT), a rate-limiting enzyme in the catabolic pathway of polyamine metabolism, is a stress-inducible gene induced by many non-steroidal anti-inflammatory drugs (NSAIDs), chemotherapy drugs and other cytokines. Induction of SSAT leads to lower intracellular polyamine contents, which have been associated with decreased cell growth and increased apoptosis. Previous studies indicated that the pleiotropic cytokine, tumor necrosis factor α (TNF□□, can induce SSAT by activating the NF□B signaling pathway in non-small cell lung cancer (NSCLC) cells. In colorectal cancer cells, SSAT can also be induced by the activation of peroxisome proliferator-activated receptor □ (PPAR□) via p38 mitogen-activated protein kinase (MAPK)-dependent mechanism under the effect of the NSAID sulindac or a natural polyphenol, resveratrol. Axl, a receptor tyrosine kinase, regulates numerous signaling pathways and inhibits cell apoptosis and promotes cancer cell proliferation and invasion. Here we show that SSAT mRNA expression and enzyme activities were down-regulated in the Axl-overexpression lung cancer cell lines. In addition, decreased invasion abilities in the SSAT-overexpression cell lines and increased invasion abilities in the SSAT-knockdown cell lines were demonstrated by invasion assays. Therefore, we proposed that there are some underlying molecular mechanisms between Axl and SSAT. We showed that SSAT gene lies in the downstream of Axl signaling by invasion assay on the Axl-overexpression cell line overexpressing SSAT. Besides, in the Axl-overexpression cell lines, coincubation with kinase inhibitors, LY294002 and U0126, revealed that the main Axl-triggered PI3K/Akt and MEK/ERK pathways may not directly influence the regulation of SSAT. On the other hand, treatment with transcription factor inhibitors, silibin and GW9662, showed that the Axl-regulated reduction of SSAT was independent of NFκB signaling, but may be due to the inactivation of PPARγ, in the cell lines with diminishing Axl signaling. These results implied that SSAT, positively regulated through the transcription factor PPARγ which is inactivated by some Axl-triggered signaling pathways, may play a role in the inhibition of cancer cell invasion and be a good target as a cancer therapy drug.