Metastatic SW620 colon cancer cells are primed for death when detached and can be sensitized to anoikis by the BH3-mimetic ABT-737
Tumour progression is the consequence of multiple genotypic and phenotypic alterations. One of these, necessary for the formation of metastasis, is acquisition of a resistance to anoïkis, a form of apoptosis triggered by loss of attachment to the extra-cellular matrix. In order to study anoïkis, we used two isogenic human colon cell lines : SW480 cells derived from the primary tumour and sensitive to anoïkis, and SW620 cells derived from a lymph node metastasis in the same patient which are resistant to anoikis. We found that anoikis signaling in SW480 cells is a form of intrinsic apoptosis thus starting at the mitochondria and under the control of Bcl-2 family proteins. Among the members of this family, the BH3-only proapoptotic protein Bim was the only one that we found to be differentially regulated between the two cell lines: whereas Bim expression augments strongly during the culture in suspension of SW480, it only slightly does so in SW620 cells. Most interestingly, despite this difference, both cell lines turned to be sensisitive to the BH3-mimetic ABT-737 but only when they are in suspension. This shows that, whether or not they a sensitive to anoikis, detached colon cancer cells are “primed for death” and thus that ABT-737 related compounds such as Navitoclax or ABT-199 might have anti-metastatic properties in solid tumours. In the second part of this work, we show that the transmembrane protein CDCP1 (CUB Domain Containing Protein 1) appears be necessary but not sufficient to protect these cells against anoïkis. CDCP1 is a Src substrate but its tyrosine phosphorylation is not involved in this protection. Finally, we have identified two new proteins interacting with CDCP1: ITGB4 and EphA2.