The effect of HIF-1[alpha] and PKM1 expression on acquisition of chemoresistance

• Published in: Cancer management and research Vol. 10; p. 1865
• Main Authors: Okazaki, Mitsuyoshi, Fushida, Sachio, Tsukada, Tomoya, Kinoshita, Jun, Oyama, Katsunobu, Miyashita, Tomoharu, Ninomiya, Itasu, Harada, Shinichi, Ohta, Tetsuo
• Format: Journal Article
• Language: English
• Published: Dove Medical Press Limited 01.01.2018
• Subjects: Cancer treatment; Chemotherapy; Diagnosis; Dosage and administration; Endothelial growth factors; Gene expression; Genetic aspects; Microbial drug resistance; Paclitaxel; Patient outcomes; Stomach cancer; Tumors; Vascular endothelial growth factor
• ISSN: 1179-1322; 1179-1322
• DOI: 10.2147/CMAR.S166136

Background: In patients with gastric cancer, one of the greatest obstacles to effective chemotherapy is the development of chemoresistance. It has been previously reported that hypoxia-inducible factor-1 alpha (HIF-1[alpha]) is associated with acquisition of chemoresistance, and more recent studies have also noted an association of pyruvate kinase muscle 1 (PKM1) and chemoresistance. The purpose of this study was to identify the effect of HIF-1[alpha] and PKM1 expression on the development of acquired chemoresistance using a paclitaxel (PTX)-resistant gastric cancer cell line. Materials and methods: A cancer cell line resistant to PTX was established from MKN45 cells by stepwise exposure to drug (rMKN45-PTX). The expressions of HIF-1[alpha], apoptosis, vascular endothelial growth factor (VEGF), multidrug transporters and glycolytic enzyme were examined by Western blotting, enzyme-linked immunosorbent assay and immunohistochemistry. We also assessed the tumor proliferation by subcutaneous tumor and peritoneal dissemination of mouse xenograft model. Results: The resistance index was 6.1 by determining as the ratio of the 50% growth inhibition (I[C.sub.50]) of rMKN45-PTX/I[C.sub.50] of MKN45. Expression of nuclear factor kappa B and HIF-1[alpha] was increased in rMKN45-PTX cells compared with the parent cells. Expression of Bax and caspase-3 was significantly downregulated, whereas expression of Bcl-xL, P-glycoprotein, multidrug resistance-associated protein and VEGF was increased in rMKN45-PTX. The expression level of PKM1 was upregulated in rMKN45-PTX, leading to an increase in the PKM1/PKM2 ratio. Using xenograft models, we demonstrated that mouse subcutaneous tumors derived from rMKN45-PTX were significantly larger than those derived from MKN45 cells. Conclusion: Under the stress of chemotherapeutic agent exposure, high expression of HIF-1[alpha] affects various downstream genes. Although the underlying mechanism is unknown, our data suggest that PKM1 is also a molecular target for gastric cancer treatment. Keywords: HIF-1[alpha], PKM1, chemoresistance, gastric cancer