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

Zheng Wang,Jun Wen,Yu Zhang,Tongtong Zhang,Qian Liu,Rui Mao,Yanjun Liu,Yi Li

doi:10.1038/s41419-022-04599-x

Abstract

Chemotherapy 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.

Highlights

Colon cancer is one of the most commonly diagnosed cancers and a leading cause of death worldwide [1]
DNAJB8 is overexpressed in L-OHP-resistant COAD cells The chemoresistant cell model (SW620/L-OHP and SW480/L-OHP) was established from the human colorectal adenocarcinoma cell mouse anti-DNAJB8 antibody (Abcam, ab235546) conjugated to AlphaLISA
We investigated the potential role of DNAJB8 in the response of COAD to L-OHP treatment and the underlying mechanisms

Summary

Introduction

Colon cancer is one of the most commonly diagnosed cancers and a leading cause of death worldwide [1]. The overall incidence and mortality rates of colon cancer have been declining; the prognosis of colon cancer remains poor [2]. Identification of novel effective chemotherapy drugs or improvement of the efficacy of anti-colon cancer drugs would be very helpful for colon cancer treatment, especially for advanced colon cancer. Oxaliplatin (L-OHP)-based chemotherapy is routinely used to treat colon cancer patients who are at high risk of recurrence or those with advanced or metastatic disease [3]. A significant proportion of patients receiving L-OHP therapy become chemoresistant. Understanding the mechanisms underlying L-OHP resistance can help us to identify a subgroup of patients who may benefit from L-OHP therapy and avoid overtreatment

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