PCDH17 increases the sensitivity of colorectal cancer to 5-fluorouracil treatment by inducing apoptosis and autophagic cell death

Shuiping Liu,Bi Chen,Yu Xiang,Hong Luo,Da Wang,Guoxiong Li,Wenzheng Zhang,Ying Liu,Bingtao Zhai,Yongqiang Li,Hui‐Ping Lin ,Xiaying Chen,Ruonan Zhang,Tian Xie,Xiao‐Jian Han ,Guohua Li,Lvjia Zhuo,Peng Chen,Liuxi Chen,Xiaohui Chen,Ting Duan,Qiang Li,Lili Yan,Ting Pan,Qiujie Li,Tengchuan Jin ,Mingming Zhang,Xingxing Huang,Yitian Sun,Wengang Wang,Jiao Feng,Qin Zhang,Jian-Shu Lou ,Xinbing Sui

doi:10.1038/s41392-019-0087-0

Abstract

5-Fluorouracil (5-FU) is known as a first-line chemotherapeutic agent against colorectal cancer (CRC), but drug resistance occurs frequently and significantly limits its clinical success. Our previous study showed that the protocadherin 17 (PCDH17) gene was frequently methylated and functioned as a tumor suppressor in CRC. However, the relationship between PCDH17 and 5-FU resistance in CRC remains unclear. Here, we revealed that PCDH17 was more highly expressed in 5-FU-sensitive CRC tissues than in 5-FU-resistant CRC tissues, and high expression of PCDH17 was correlated with high BECN1 expression. Moreover, this expression profile contributed to superior prognosis and increased survival in CRC patients. Restoring PCDH17 expression augmented the 5-FU sensitivity of CRC in vitro and in vivo by promoting apoptosis and autophagic cell death. Furthermore, autophagy played a dominant role in PCDH17-induced cell death, as an autophagy inhibitor blocked cell death to a greater extent than the pancaspase inhibitor Z-VAD-FMK. PCDH17 inhibition by siRNA decreased the autophagy response and 5-FU sensitivity. Mechanistically, we showed that c-Jun NH2-terminal kinase (JNK) activation was a key determinant in PCDH17-induced autophagy. The compound SP600125, an inhibitor of JNK, suppressed autophagy and 5-FU-induced cell death in PCDH17-reexpressing CRC cells. Taken together, our findings suggest for the first time that PCDH17 increases the sensitivity of CRC to 5-FU treatment by inducing apoptosis and JNK-dependent autophagic cell death. PCDH17 may be a potential prognostic marker for predicting 5-FU sensitivity in CRC patients.

Highlights

Colorectal cancer (CRC) ranks third in morbidity and second in mortality among various malignancies, much progress has been achieved in CRC therapy in past years.[1]
Because we observed that autophagic cell death was involved in the effect of protocadherin 17 (PCDH17) on CRC cell viability, we detected the protein levels of phosphorylatedJNK (p-Jun N-terminal kinase (JNK)) to determine whether the JNK pathway is activated in PCDH17-transfected cells when exposed to 5-FU treatment
5-FU-based chemotherapy remains widely used in the clinical treatment of CRC patients, but resistance to 5-FU is a major drawback in its clinical use.[16]

Summary

1234567890();,: INTRODUCTION

Colorectal cancer (CRC) ranks third in morbidity and second in mortality among various malignancies, much progress has been achieved in CRC therapy in past years.[1]. In line with the above findings, flow cytometry results showed that PCDH17 knockdown significantly decreased 5-FU sensitivity in HCT116/PCDH17 and SW480/PCDH17 cells (Fig. 4j, k) Taken together, these data suggested that PCDH17 could modulate autophagy and augment the 5-FU sensitivity of CRC cells. JNK activation can mediate BECN1 expression to induce autophagic cell death in response to chemotherapeutic agents.[15] Because we observed that autophagic cell death was involved in the effect of PCDH17 on CRC cell viability, we detected the protein levels of phosphorylatedJNK (p-JNK) to determine whether the JNK pathway is activated in PCDH17-transfected cells when exposed to 5-FU treatment. Inhibition of autophagy by JNK knockdown attenuated the cytotoxicity activity of 5-FU (Fig. 6d) These results demonstrated that PCDH17-induced autophagic cell death by activating the JNK signaling pathway

DISCUSSION

Findings

METHODS