DNAJB8 in small extracellular vesicles promotes Oxaliplatin resistance through TP53/MDR1 pathway in colon cancer

Abstract

AbstractChemotherapy is one of the most frequently used therapies for the treatment of colon cancer (COAD). However, Oxaliplatin (L-OHP) resistance is a major obstacle to the effective treatment of COAD. Here, we investigated whether DNAJB8, a heat shock protein 40 (HSP40) family protein, could be used for the prognosis and therapy of L-OHP resistance in COAD. Treatment with small interfering RNA targeting DNAJB8 could restore the response to L-OHP in vitro and in vivo. On the mechanism, we demonstrated that DNAJB8 could interact with TP53 and inhibit the ubiquitination degradation of TP53, leading to MDR1 upregulation which promotes colon cancer L-OHP resistance. We found that small extracellular vesicle (sEV)-mediated transfer of DNAJB8 from L-OHP-resistant COAD cells to sensitive cells contributed to L-OHP resistance. A prognostic signature based on the DNAJB8 levels in both tissue and serum showed that COAD patients with high-risk scores exhibited significantly worse overall survival and disease-free survival than patients with low-risk scores. These results indicate that DNAJB8 levels in serum sEVs may serve as a biomarker for COAD. DNAJB8 from sEVs might be a promising therapeutic target for L-OHP resistance and a prognostic predictor of clinical response.