Abstract
Oxaliplatin is a commonly used chemotherapeutic drug for the treatment of advanced colorectal cancer. However, acquired drug resistance against oxaliplatin remains a major obstacle for efficient use of it, and mechanisms underlying oxaliplatin resistance are still required to be explored. In the present study, we exposed colorectal cancer cell line SW480 to oxaliplatin for a long time to obtain oxaliplatin-resistant colorectal cancer cell model (OR-SW480). We found that intracellular expression of miR-29b was decreased when the SW480 cells became oxaliplatin-resistant. More importantly, overexpression of miR-29b resensitized OR-SW480 cells to oxaliplatin treatment. Mechanically, gene of SIRT1 was identified to be the target of miR-29b. Overexpression of miR-29b in oxaliplatin-treated OR-SW480 decreased the expression of SIRT1 to enhance the ROS production and JNK phosphorylation, and thus promoting apoptosis via activation of caspase 9, 7 and 3. On the other hand, expression plasmid of SIRT1, N-acetyl cysteine or SP600125 (JNK specific inhibitor) abolished the effect of miR-29b on oxaliplatin-treated OR-SW480. We therefore demonstrated that miR-29b reverses oxaliplatin-resistance in colorectal cancer by targeting SIRT1/ROS/JNK pathway.
Highlights
Colorectal cancer (CRC) is the third common malignancies, which represents the second leading cause of cancer-associated mortality worldwide [1, 2]
The results showed that expression of miR-29b reduced by 77.1 percent in OR-SW480 and 59.2 percent in OR’-SW480 compared to SW480 cells (Figure 1B)
We demonstrated that expression level of miR-29b was associated with oxaliplatin sensitivity, and overexpression of miR-29b was able to reverse the oxaliplatin-resistance in CRC
Summary
Colorectal cancer (CRC) is the third common malignancies, which represents the second leading cause of cancer-associated mortality worldwide [1, 2]. Surgical therapy is the most effective treatment for CRC, patients with colorectal cancer are usually diagnosed in an advanced stage, because CRC is characterized by early metastasis and late apparent symptom [3, 4]. For these advanced CRC patients, chemotherapy is considered as the preferred treatment. Long-term use of chemotherapeutic agents induces acquired drug resistance in cancers including colorectal cancer [5, 6]. Oxaliplatin is a commonly used chemotherapeutic drug for the treatment of advanced colorectal cancer Mechanisms underlying chemoresistance are required to be investigated, and strategies are urgent to be explored to increase the chemosensitivity of CRC cells.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
