Hirao Takuya, Yamaguchi Masashi, Kikuya Megumi, Chibana Hiroji, Ito Kousei, Aoki Shigeki
Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
Medical Mycology Research Center, Chiba University, Chiba, Japan.
Cancer Sci. 2018 Jan;109(1):121-131. doi: 10.1111/cas.13442. Epub 2017 Dec 7.
Tyrosine kinase inhibitors (TKI), including imatinib (IM), improve the outcome of CML therapy. However, TKI treatment is long-term and can induce resistance to TKI, which often leads to a poor clinical outcome in CML patients. Here, we examined the effect of continuous IM exposure on intracellular energy metabolism in K562 cells, a human Philadelphia chromosome-positive CML cell line, and its subsequent sensitivity to anti-cancer agents. Contrary to our expectations, we found that continuous IM exposure increased sensitivity to TKI. Cancer energy metabolism, characterized by abnormal glycolysis, is linked to cancer cell survival. Interestingly, glycolytic activity was suppressed by continuous exposure to IM, and autophagy increased to maintain cell viability by compensating for glycolytic suppression. Notably, increased sensitivity to TKI was not caused by glycolytic inhibition but by altered intracellular signaling, causing glycolytic suppression and increased autophagy, as evidenced by suppression of p70 S6 kinase 1 (S6K1) and activation of AMP-activated protein kinase (AMPK). Using another human CML cell line (KCL22 cells) and BCR/ABL+ Ba/F3 cells (mimicking Philadelphia chromosome-positive CML cells) confirmed that suppressing S6K1 and activating AMPK increased sensitivity to TKI. Furthermore, suppressing S6K1 and activating AMPK had a synergistic anti-cancer effect by inhibiting autophagy in the presence of TKI. The present study provides new insight into the importance of signaling pathways that affect cellular energy metabolism, and suggests that co-treatment with agents that disrupt energy metabolic signaling (using S6K1 suppressors and AMPK activators) plus blockade of autophagy may be strategies for TKI-based CML therapy.
酪氨酸激酶抑制剂（TKI），包括伊马替尼（IM），可改善慢性粒细胞白血病（CML）的治疗效果。然而，TKI治疗是长期的，并且会诱导对TKI的耐药性，这常常导致CML患者临床预后不良。在此，我们研究了持续暴露于IM对K562细胞（一种人费城染色体阳性的CML细胞系）细胞内能量代谢的影响及其随后对抗癌药物的敏感性。与我们的预期相反，我们发现持续暴露于IM会增加对TKI的敏感性。以异常糖酵解为特征的癌症能量代谢与癌细胞存活相关。有趣的是，持续暴露于IM会抑制糖酵解活性，并且自噬增加以通过补偿糖酵解抑制来维持细胞活力。值得注意的是，对TKI敏感性的增加不是由糖酵解抑制引起的，而是由细胞内信号改变导致的，这种改变导致糖酵解抑制和自噬增加，这通过抑制p70 S6激酶1（S6K1）和激活AMP活化蛋白激酶（AMPK）得到证实。使用另一种人CML细胞系（KCL22细胞）和BCR/ABL+ Ba/F3细胞（模拟费城染色体阳性的CML细胞）证实，抑制S6K1和激活AMPK会增加对TKI的敏感性。此外，在存在TKI的情况下，抑制S6K1和激活AMPK通过抑制自噬具有协同抗癌作用。本研究为影响细胞能量代谢的信号通路的重要性提供了新的见解，并表明联合使用破坏能量代谢信号的药物（使用S6K1抑制剂和AMPK激活剂）以及阻断自噬可能是基于TKI的CML治疗策略。
