Introduction: Kallikrein 11 (KLK11) plays a crucial role in drug-resistance to oxaliplatin (L-OHP) in the treatment of metastatic colorectal cancer (mCRC). The study aimed to investigate the role of KLK11 in chemoresistance, and to clarify the mechanism underlying reverse of L-OHP resistance by knockdown of KLK11.
Materials and Methods: Resistance to oxaliplatin was induced in HCT-8 (HCT-8/L-OHP) colorectal adenocarcinoma cell lines by exposing cells to increasing concentrations of L-OHP. MTT, RT-qPCR, and Western blot were used to evaluate the resistance to L-OHP. We then knocked down KLK11 in HCT-8/L-OHP cells to explore the mechanism through which KLK11 reverses L-OHP resistance. The mRNA and protein expression of KLK11 in tissues from mCRC patients were detected by RT-qPCR and immunohistochemistry.
Results: The drug resistance index (RI) of HCT-8/L-OHP cell line to L-OHP, 5-Fluorouracil (5-FU), Irinotecan (CPT-11), Vincristine (VCR) and Cis-diamminedichloroplatinum (CDDP) were 10, 5.35, 3.23, 1.28, and 6.64, respectively. Increased expression of multi-drug resistant genes ABCC1 , ABCB1 , GSTP1  and ERCC1  were detected in HCT-8/L-OHP cell line. Moreover, the activated PI3K/AKT pathway was related to L-OHP-resistance. Knockdown of KLK11  in HCT-8/L-OHP cell reversed L-OHP-resistance by inhibiting cell growth and activating apoptosis via suppressing the PI3K/AKT signaling pathway. Moreover, high expression of KLK11 in chemoresistant-patients was associated with lymph node metastases and histopathology.
Conclusion: KLK11 was highly expressed in chemoresistant-patients and L-OHP-resistant cell lines. Moreover, L-OHP resistance was associated with activated PI3K/AKT signal pathway. Knockdown of KLK11  can reverse L-OHP resistance by blocking PI3K/AKT signaling pathway.
Keywords: colorectal cancer, kallikrein 11, oxaliplatin, drug resistance, apoptosis