Integrative Analysis of Subcellular Quantitative Proteomics Studies Reveals Functional Cytoskeleton Membrane–Lipid Raft Interactions in Cancer

Lipid
rafts are dynamic membrane microdomains that orchestrate
molecular interactions and are implicated in cancer development. To
understand the functions of lipid rafts in cancer, we performed an
integrated analysis of quantitative lipid raft proteomics data sets
modeling progression in breast cancer, melanoma, and renal cell carcinoma.
This analysis revealed that cancer development is associated with
increased membrane raft–cytoskeleton interactions, with ∼40%
of elevated lipid raft proteins being cytoskeletal components. Previous
studies suggest a potential functional role for the raft–cytoskeleton
in the action of the putative tumor suppressors PTRF/Cavin-1 and Merlin.
To extend the observation, we examined lipid raft proteome modulation
by an unrelated tumor suppressor opioid binding protein cell-adhesion
molecule (OPCML) in ovarian cancer SKOV3 cells. In agreement with
the other model systems, quantitative proteomics revealed that 39%
of OPCML-depleted lipid raft proteins are cytoskeletal components,
with microfilaments and intermediate filaments specifically down-regulated.
Furthermore, protein–protein interaction network and simulation
analysis showed significantly higher interactions among cancer raft
proteins compared with general human raft proteins. Collectively,
these results suggest increased cytoskeleton-mediated stabilization
of lipid raft domains with greater molecular interactions as a common,
functional, and reversible feature of cancer cells.