Abstract
Exosomes are cell-derived nanovesicles, and lately, cancer-derived exosomes have been reported to carry KRAS protein, which contributes to the malignancy of many cancers. In this study, farnesylthiosalicylic acid (FTS) was used to inhibit the activities of mutated KRAS in colon cancer SW480 cells to discover the potential link between KRAS activities and cancer-derived exosomes. We observed that FTS inhibits KRAS activity in SW480 cells, but promotes their exosome production. When the exosomal proteins of SW480 cells were profiled, a total of 435 proteins were identified with 16 of them showing significant changes (greater than or equal to two-fold) in response to FTS treatment. Protein network analysis suggests KRAS inhibition may trigger stress in the cells. In addition, a high level of acetyl-coA synthetase family member 4 protein which plays an important role in colon cancer survival was identified in the exosomes secreted by FTS-treated SW480 cells. The uptake of these exosomes suppresses the growth of some cell types, but in general exosomes from FTS-treated cells enhance the recipient cell survival when compared to that of untreated cells. Together our findings suggest that FTS may trigger stress in SW480 cells, and induce more exosomes secretion as the survival messenger to mitigate the impact of KRAS inhibition in colon cancer cells.
Highlights
KRAS is one of the most prominent oncogenes found in many cancer cell types, predominantly in colon, pancreas and lung cancers [1,2]
Previous studies found that the invasive properties of mutated KRAS-bearing colon cancer cells were highly associated with Rho family GTPases (RAS homolog), which play a significant role in altering actin organization, cell-cell interaction and cell adhesion, resulting in the development of invasive properties in the cancer cells
Suppression of KRAS activity could significantly induce the expression of p53 in cells [18]. Consistent with this previous finding, Western blot analysis in our study showed that farnesylthiosalicylic acid (FTS) treatment increased p53 in SW480 cells, implying that KRAS inhibition by FTS may trigger stress in the colon cancer cells, and p53 as a stress sensor [19] could possibly mediate the secretion of more exosomes as a cellular response to the intervention
Summary
KRAS is one of the most prominent oncogenes found in many cancer cell types, predominantly in colon, pancreas and lung cancers [1,2]. Members of the Rho family GTPases (RhoA, Rac and Cdc42) were found to be involved in the transducing of intracellular signals to modulate a wide spectrum of cellular processes, including vesicle trafficking, which is important for the biogenesis of multivesicular bodies (MVB) [5]. Colon cancer-derived exosomes were found to promote cancer cell proliferation under hypoxic conditions through the activation of the STAT3 signaling pathway and the shortening of the mitotic stage [9]. Another study found that the exosomes derived from mutated KRAS-bearing colon cancer promoted the growth of non-transformed cells bearing wild-type KRAS. These exosomes enhanced the invasiveness of the recipient cells compared to exosomes derived from wild type KRAS-bearing colon cancer cells [10]
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