Adjuvant chemotherapy is an essential component in the treatment of advanced colorectal cancer (CRC). Unfortunately, many patients experience recurrence with aggressive, chemotherapy-resistant disease for which the prognosis is poor and treatment options are limited. Understanding the changes that cancer cells undergo during the acquisition of a drug-resistant phenotype is therefore of critical importance in improving CRC patient outcomes. We chose to study resistance to the CRC chemotherapy agent, irinotecan, by first creating a CRC cell line that is highly resistant to its active metabolite (SN-38). In particular, we were interested in how SN-38 resistant CRC cells (HT-29S) were altered from parental, drug-sensitive CRC cells (HT-29) in their relationship with a feature of their microenvironment, the extracellular matrix (ECM). We found that HT-29S cells form a matrix composed of the ECM glycoprotein fibronectin when cultured as 3-dimensional spheroids, whereas HT-29 cells do not. The increase in fibronectin matrix deposition coincided with an increased fibronectin adhesive capacity of the SN-38-resistant cells, likely due to an increased expression of the integrin α5 subunit, which together with integrin β1 forms the primary fibronectin receptor. Furthermore, we demonstrated an activation of a phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) pro-survival signalling pathway downstream of integrin α5β1 ligation to fibronectin. Inhibition of this signalling pathway with the PI3K inhibitor LY294002 sensitized HT-29S cells to SN-38, but did not alter the response of the parental cell line to the chemotherapy agent. Finally, we have determined that HT-29S cells appear to undergo an epithelial to mesenchymal transition during the acquisition of chemotherapy resistance, and that this transition may be responsible for the upregulation of integrin α5 in the resistant population
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