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

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 (<i>PCDH17</i>) gene was frequently methylated and functioned as a tumor suppressor in CRC. However, the relationship between <i>PCDH17</i> and 5-FU resistance in CRC remains unclear. Here, we revealed that <i>PCDH17</i> was more highly expressed in 5-FU-sensitive CRC tissues than in 5-FU-resistant CRC tissues, and high expression of <i>PCDH17</i> was correlated with high BECN1 expression. Moreover, this expression profile contributed to superior prognosis and increased survival in CRC patients. Restoring <i>PCDH17</i> 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 <i>PCDH17</i>-induced cell death, as an autophagy inhibitor blocked cell death to a greater extent than the pancaspase inhibitor Z-VAD-FMK. <i>PCDH17</i> 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 <i>PCDH17</i>-induced autophagy. The compound SP600125, an inhibitor of JNK, suppressed autophagy and 5-FU-induced cell death in <i>PCDH17</i>-reexpressing CRC cells. Taken together, our findings suggest for the first time that <i>PCDH17</i> increases the sensitivity of CRC to 5-FU treatment by inducing apoptosis and JNK-dependent autophagic cell death. <i>PCDH17</i> may be a potential prognostic marker for predicting 5-FU sensitivity in CRC patients.