ROS/JNK/C-Jun Pathway is Involved in Chaetocin Induced Colorectal Cancer Cells Apoptosis and Macrophage Phagocytosis Enhancement.

Huihui Wang,Xiangling Yang,Wende Li,Fang Wang,Huanliang Liu,Weiqian Li,Junsheng Peng,Qiyuan Qin,Weibiao Ye,Siyu Chen,Junxiong Chen,Lu He,Chuangyu Wen

doi:10.3389/fphar.2021.729367

Abstract

There is an urgent need for novel agents for colorectal cancer (CRC) due to the increasing number of cases and drug-resistance related to current treatments. In this study, we aim to uncover the potential of chaetocin, a natural product, as a chemotherapeutic for CRC treatment. We showed that, regardless of 5-FU-resistance, chaetocin induced proliferation inhibition by causing G2/M phase arrest and caspase-dependent apoptosis in CRC cells. Mechanically, our results indicated that chaetocin could induce reactive oxygen species (ROS) accumulation and activate c-Jun N-terminal kinase (JNK)/c-Jun pathway in CRC cells. This was confirmed by which the JNK inhibitor SP600125 partially rescued CRC cells from chaetocin induced apoptosis and the ROS scavenger N-acetyl-L-cysteine (NAC) reversed both the chaetocin induced apoptosis and the JNK/c-Jun pathway activation. Additionally, this study indicated that chaetocin could down-regulate the expression of CD47 at both mRNA and protein levels, and enhance macrophages phagocytosis of CRC cells. Chaetocin also inhibited tumor growth in CRC xenograft models. In all, our study reveals that chaetocin induces CRC cell apoptosis, irrelevant to 5-FU sensitivity, by causing ROS accumulation and activating JNK/c-Jun, and enhances macrophages phagocytosis, which suggests chaetocin as a candidate for CRC chemotherapy.

Highlights

Colorectal cancer (CRC) is one of the most frequently diagnosed cancer in the world (Sung et al, 2021)
Realtime cell analysis showed that the normalized cell index was inhibited by chaetocin in a dose-dependent manner in HCT116, LS174T and LIM1215 cells (Figure 1B), indicating that the cell proliferation of colorectal cancer (CRC) cells was markedly restrained by chaetocin
Our results showed that macrophages had an enhanced phagocytosis of HCT116 cells which were pretreated with chaetocin (Figure 7D), indicating that chaetocin could reduce the expression of Cluster of differentiation 47 (CD47) in CRC cells and enhance macrophages phagocytosis of CRC cells

Summary

Introduction

Colorectal cancer (CRC) is one of the most frequently diagnosed cancer in the world (Sung et al, 2021). The clinical options available for CRC include surgery, radiotherapy, chemotherapy, targeted therapy and immunotherapy (Dekker et al, 2019). 5-FU remains the first-line chemo drug for CRC, but resistance and adverse side effects significantly limit its efficacy (Biagi et al, 2011). Graph abstract | Schematic representation of the mechanism of the action of chaetocin in CRC cells. Molecular targeted agents like cetuximab, a epidermal growth factor receptor inhibitor, have been approved for CRC patients, high mutation rates of KRAS and BRAF result in unsatisfactory effects of these drugs (Gunjur, 2019). Due to the particular feature of CRC, the effectiveness of immunotherapy includes PD-1/PDL1 inhibitors is really limited on CRC patients (Ganesh et al, 2019). Metastasis and drug resistance may benefit from the moderate increase in ROS levels, but excessive ROS accumulation causes cancer cell death, and cancer cells preserves a higher concentration of ROS comparing to that in their normal counterparts (Tafani et al, 2016; Galadari et al, 2017)

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