CD147 supports paclitaxel resistance via interacting with RanBP1

Gang Nan,Dong Chao,Shu-Hua Zhao,Wen-Jing Wang,Xin Fu,Hong-Yong Cui,Xi Chen,Zhi-Nan Chen,Ruo-Fei Tian,Shi-Jie Wang,Peng Lin,Ting Wang,Ting Guo,Xiu-Xuan Sun,Bin Wang

doi:10.1038/s41388-021-02143-3

Abstract

Though the great success of paclitaxel, the variable response of patients to the drug limits its clinical utility and the precise mechanisms underlying the variable response to paclitaxel remain largely unknown. This study aims to verify the role and the underlying mechanisms of CD147 in paclitaxel resistance. Immunostaining was used to analyze human non-small-cell lung cancer (NSCLC) and ovarian cancer tissues. RNA-sequencing was used to identify downstream effectors. Annexin V-FITC/propidium iodide and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to detect apoptosis. Co-immunoprecipitation (Co-IP), fluorescence resonance energy transfer (FRET) and surface plasmon resonance (SPR) were performed to determine protein interactions. Fluorescence recovery after photobleaching (FRAP) was performed to measure the speed of microtubule turnover. Xenograft tumor model was established to evaluate sensitivity of cancer cells to paclitaxel in vivo. In vitro and in vivo assays showed that silencing CD147 sensitized the cancer cells to paclitaxel treatment. CD147 protected cancer cells from paclitaxel-induced caspase-3 mediated apoptosis regardless of p53 status. Truncation analysis showed that the intracellular domain of CD147 (CD147ICD) was indispensable for CD147-regulated sensitivity to paclitaxel. Via screening the interacting proteins of CD147ICD, Ran binding protein 1 (RanBP1) was identified to interact with CD147ICD via its C-terminal tail. Furthermore, we showed that RanBP1 mediated CD147-regulated microtubule stability and dynamics as well as response to paclitaxel treatment. These results demonstrated that CD147 regulated paclitaxel response by interacting with the C-terminal tail of RanBP1 and targeting CD147 may be a promising strategy for preventing paclitaxel resistant.

Highlights

Microtubules, highly dynamic components of the cytoskeleton, participate in multiple cellular activities
CD147ICD interacts with related nuclear protein (Ran) binding protein 1 (RanBP1) We showed that CD147 regulates paclitaxel resistance via its intracellular domain
The impairment induced by CD147 overexpression was restored, at least partially, by RanBP1 silence. All these results indicate that CD147 is involved in regulation of microtubule stability and dynamics and this regulation is mediated by RanBP1

Summary

Introduction

Microtubules, highly dynamic components of the cytoskeleton, participate in multiple cellular activities. Dysregulation of microtubule dynamics contributes to the development of serious diseases, including cancer. Microtubule dynamics is one of the major targets for chemotherapeutic agents. Since its approval by the FDA in 1992 for the treatment of ovarian cancer, the use of paclitaxel has led to dramatically improvement in the duration and quality of life for many cancer patients, the majority eventually develop progressive disease after initially responding to paclitaxel treatment. While a variety of mechanisms have been linked to paclitaxel resistance, including overexpression of ATP-dependent translocase ABCB1 [1], mutations in drug binding sites on tubulin [2,3,4,5,6,7], alterations in tubulin isotype distribution [8], aberrant expression of noncoding RNAs [9], impairment of apoptotic pathways [10] and altered expression of microtubule regulatory proteins [11], the mechanisms responsible for paclitaxel resistance are far from clear

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