KLF5 Inhibition Overcomes Oxaliplatin Resistance in Patient-derived Colorectal Cancer Organoids by Restoring Apoptotic Response

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2022 Apr 5

PMID 35379798

Authors

Xiaohui Shen

Yuchen Zhang

Zhuoqing Xu

Han Gao

Wenqing Feng

Wenchang Li

Yiming Miao

Zifeng Xu

Yaping Zong

Jingkun Zhao

Aiguo Lu

Affiliations

Soon will be listed here.

Abstract

Oxaliplatin resistance is a major challenge in the treatment of colorectal cancer (CRC). Many molecular targeted drugs for refractory CRC have been developed to solve CRC drug resistance, but their effectiveness and roles in the progression of CRC and oxaliplatin resistance remain unclear. Here, we successfully constructed CRC PDOs and selected the Kruppel-like factor 5 (KLF5) inhibitor ML264 as the research object based on the results of the in vitro drug screening assay. ML264 significantly restored oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response, and this effect was achieved by inhibiting the KLF5/Bcl-2/caspase3 signaling pathway. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays verified that KLF5 promoted the transcription of Bcl-2 in CRC cells. KLF5 inhibition also overcame oxaliplatin resistance in xenograft tumors. Taken together, our study demonstrated that ML264 can restore oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response. KLF5 may be a potential therapeutic target for oxaliplatin-resistant CRC. PDOs have a strong potential for evaluating inhibitors and drug combination therapy in a preclinical environment.

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