Caveolin-1 is associated with acquired selumetinib resistance and altered EGFR signaling in colorectal cancer cells.

Abstract

Acquired resistance remains a major limitation to the sustained efficacy of mitogen-activated protein kinase kinase (MEK) inhibition in colorectal cancer (CRC), but the molecular adaptations associated with this phenotype remain incompletely defined. This pilot study investigated the association of Caveolin-1 with acquired resistance to the MEK1/2 inhibitor selumetinib, and epidermal growth factor receptor (EGFR) signaling. Selumetinib-resistant derivatives of HT-29 and SW480 CRC cells were generated by prolonged drug exposure. CAV1 mRNA and Caveolin-1 protein expression were assessed by reverse transcription-quantitative PCR and western blotting, respectively, and the functional relevance of Caveolin-1 was examined using independent short hair RNA-mediated knockdown approaches. CAV1 mRNA and Caveolin-1 protein expression were consistently upregulated in selumetinib-resistant cells compared with their parental counterparts. Caveolin-1 depletion impaired proliferation of resistant cells and, in the presence of selumetinib, further reduced cell viability and enhanced apoptotic responses, as evidenced by increased caspase-3/7 activity and cleavage of PARP and caspase-3. In HT-29/SR cells, Caveolin-1 depletion was associated with altered EGF-induced EGFR and GSK-3α/β phosphorylation. These findings identify Caveolin-1 upregulation as a feature of the experimentally established selumetinib-resistant phenotype and suggest a functional association between Caveolin-1 and cellular responses to sustained MEK inhibition. However, the signaling observations were limited to HT-29/SR cells and do not establish EGFR-dependent causality. Further validation in independently derived resistant populations and physiologically relevant models is required to determine the mechanistic and translational significance of these findings.