The
S-phase kinase-associated protein 2 (SKP2)
oncoprotein is an
E3 ubiquitin ligase. Overexpression of SKP2 was found in various human
cancers, including
colorectal cancers, but its potential role as a prognostic marker after
neoadjuvant chemoradiotherapy (CRT) and for therapeutic intervention in
rectal cancers is unknown. This study examined the correlation of SKP2 expression in the prognosis of
rectal cancer patients and the viability of
colorectal cancer cells treated with CRT. SKP2 immunoexpression was retrospectively assessed in pretreatment biopsies of 172
rectal cancer patients treated with neoadjuvant CRT followed by surgery. Results were correlated with clinicopathological features, therapeutic responses, and patient survival. Pharmacologic assays were used to evaluate the therapeutic relevance of
Bortezomib in two
colorectal cancer cell lines (HT-29 and SW480). High expression of SKP2 was correlated with the advanced Post-Tx nodal status (p = 0.002), Post-Tx International Union for
Cancer Control stage (p = 0.002), and a lower-degree
tumor regression grade (p < 0.001). Moreover, high expression of SKP2 (p = 0.027, hazard ratio 3.21) was an independent prognostic factor for local recurrence-free survival. In vitro,
Bortezomib downregulated SKP2 expression, induced
caspase activation, and decreased the viability of
colorectal cancer cells with or without a combination with
fluorouracil.
Bortezomib also promoted
caspase activation and gamma-H2AX formation in
colorectal cancer cells concurrently treated with CRT. High expression of SKP2 was associated with a poor therapeutic response and adverse outcomes in
rectal cancer patients treated with neoadjuvant CRT. In the presence of
chemotherapy with or without
radiotherapy, the promoted sensitivity of
colorectal cancer cells to
Bortezomib with an SKP2-repressing effect indicated that it is a potential therapeutic target.