Fukuda Shuichi, Miyata Hiroshi, Miyazaki Yasuhiro, Makino Tomoki, Takahashi Tsuyoshi, Kurokawa Yukinori, Yamasaki Makoto, Nakajima Kiyokazu, Takiguchi Shuji, Mori Masaki, Doki Yuichiro
Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Ann Surg Oncol. 2015 Dec;22 Suppl 3:S1461-8. doi: 10.1245/s10434-015-4522-3. Epub 2015 Mar 26.
Pyruvate kinase M2 (PKM2) is a key glycolytic enzyme that regulates the Warburg effect and is necessary for tumor growth. However, its role in chemoresistance has not been fully elucidated.
PKM2 expression was examined by immunohistochemistry in 205 tissue samples from thoracic esophageal squamous cell carcinoma patients who had undergone curative surgery (100 patients with surgery alone and 105 patients with preoperative chemotherapy). The relationship between PKM2 expression and clinicopathological factors, including chemotherapy response was examined. In vitro assays were performed to determine the mechanism of PKM2-related chemoresistance, using esophageal squamous cell carcinoma cell lines.
PKM2 expression significantly correlated with tumor cell differentiation, tumor depth, and tumor stage. Strong PKM2 expression significantly correlated with decreased survival rates and poor response to chemotherapy. In vitro assays showed that PKM2 inhibition significantly decreased cisplatin resistance and increased apoptosis. In siPKM2-transfected cells, pyruvate kinase activity paradoxically increased, followed by increased intracellular reactive oxygen species levels. The ratio of NADPH/NADP, which is an indicator of glucose influx into pentose phosphate pathway (PPP), significantly decreased in siPKM2-transfected cells upon cisplatin treatment compared with control cells.
PKM2 expression is associated with esophageal squamous cell carcinoma chemoresistance. PKM2 inhibition can restore cisplatin sensitivity by inactivating PPP.
丙酮酸激酶M2（PKM2）是一种关键的糖酵解酶，可调节瓦伯格效应，对肿瘤生长至关重要。然而，其在化疗耐药中的作用尚未完全阐明。
采用免疫组织化学法检测205例接受根治性手术的胸段食管鳞状细胞癌患者（100例单纯手术患者和105例术前化疗患者）组织样本中的PKM2表达。研究PKM2表达与包括化疗反应在内的临床病理因素之间的关系。利用食管鳞状细胞癌细胞系进行体外实验，以确定PKM2相关化疗耐药的机制。
PKM2表达与肿瘤细胞分化、肿瘤深度和肿瘤分期显著相关。PKM2高表达与生存率降低和化疗反应差显著相关。体外实验表明，PKM2抑制可显著降低顺铂耐药性并增加细胞凋亡。在转染siPKM2的细胞中，丙酮酸激酶活性反而增加，随后细胞内活性氧水平升高。与对照细胞相比，顺铂处理后转染siPKM2的细胞中，作为葡萄糖进入磷酸戊糖途径（PPP）指标的NADPH/NADP比值显著降低。
PKM2表达与食管鳞状细胞癌化疗耐药相关。PKM2抑制可通过使PPP失活来恢复顺铂敏感性。
