Pancreatic ductal
adenocarcinoma (PDAC) has a dismal prognosis
due to the absence of diagnostic markers and molecular targets. Here,
we took an unconventional approach to identify new molecular targets
for pancreatic cancer. We chose uncharacterized protein evidence level
1 without function annotation from extensive proteomic research on
pancreatic cancer and focused on proline and serine-rich 2 (PROSER2),
which ranked high in the cell membrane and cytoplasm. In our study
using cell lines and patient-derived orthotopic xenograft cells, PROSER2
exhibited a higher expression in cells derived from primary tumors
than in those from metastatic tissues. PROSER2 was localized in the
cell membrane and cytosol by immunocytochemistry. PROSER2 overexpression
significantly reduced the metastatic ability of cancer cells, whereas
its suppression had the opposite effect. Proteomic analysis revealed
that PROSER2 interacts with STK25 and PDCD10, and their binding was
confirmed by immunoprecipitation and immunocytochemistry. STK25 knockdown
enhanced metastasis by decreasing p-AMPK levels, whereas PROSER2-overexpressing
cells increased the level of p-AMPK, indicating that PROSER2 suppresses
invasion via the AMPK pathway by interacting with STK25. This is the
first demonstration of the novel role of PROSER2 in antagonizing tumor
progression via the STK25-AMPK pathway in PDAC. LC–MS/MS data
are available at MassIVE (MSV000092953) and ProteomeXchange (PXD045646).