Jiang Shanshan, Luo Yunfei, Zhan Zhan, Tang Zhimin, Zou Junrong, Ying Ying, Lin Hui, Huang Deqiang, Luo Lingyu
Institute of Digestive Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, China; Jiangxi Provincial Key Laboratory of Tumor Pathogens and Molecular Pathology, Department of Pathophysiology, Schools of Basic Sciences, Nanchang University, China; Institute of Hematological Research, Shaanxi Provincial People's Hospital, Xi'an, China.
Jiangxi Provincial Key Laboratory of Tumor Pathogens and Molecular Pathology, Department of Pathophysiology, Schools of Basic Sciences, Nanchang University, China.
Cell Signal. 2022 Mar;91:110215. doi: 10.1016/j.cellsig.2021.110215. Epub 2021 Dec 15.
Paclitaxel (PTX) is a common antineoplastic drug whose functionality is often restricted by drug resistance. Solute carrier organic anion transporter family member 1B3 (SLCO1B3) is a PTX influx transporter and its low expression has been proved to be relevant with PTX resistance. It has been widely reported that AMP-activated protein kinase (AMPK) could re-sensitize tumor cells to PTX. Our gene array result demonstrates AMPK up-regulated SLCO1B3. In this paper, we have tried to explain the relationships between PTX, SLCO1B3 and AMPK. First, we have verified the proliferative inhibition of PTX on A549 and found that PTX could inhibit A549 cells proliferation. Then, we have explored the relationship between SLCO1B3 and PTX: SLCO1B3 expression significantly decreased when A549 cells were treated with PTX or in A549 PTX resistant cells (A549-PTX) and the intracellular PTX concentration in A549-PTX was also lower. When treated with metformin/LKB1, both SLCO1B3 expression and intracellular PTX concentration have increased. Knockdown of AMPK has induced decreased SLCO1B3 expression. Moreover, in vitro and in vivo experiments have showed that metformin not only obviously inhibited A549-PTX tumor xenograft and A549-PTX proliferation alone, but also enhanced PTX efficacy to A549-PTX and this may be relevant to SLCO1B3. To verify it, we have treated A549 cells with AMPK both activators and an inhibitor, and then found that AMPK activators could weaken the PTX effect in inhibiting SLCO1B3 while its inhibitor has opposite effect. With knockdown of SLCO1B3, the effect of AMPK in re-sensitizing A549 to paclitaxel has decreased. To sum up, activation of AMPK can up-regulate SLCO1B3 expression, enhance the sensitivity of A549 cells to PTX, providing a new way to re-sensitize PTX resistance.
紫杉醇（PTX）是一种常见的抗肿瘤药物，其功能常受耐药性限制。溶质载体有机阴离子转运体家族成员1B3（SLCO1B3）是一种PTX流入转运体，其低表达已被证明与PTX耐药有关。大量报道表明，AMP激活的蛋白激酶（AMPK）可使肿瘤细胞对PTX重新敏感。我们的基因阵列结果显示AMPK上调了SLCO1B3。在本文中，我们试图解释PTX、SLCO1B3和AMPK之间的关系。首先，我们验证了PTX对A549细胞的增殖抑制作用，发现PTX可抑制A549细胞增殖。然后，我们探讨了SLCO1B3与PTX的关系：用PTX处理A549细胞或在A549 PTX耐药细胞（A549-PTX）中，SLCO1B3表达显著降低，且A549-PTX细胞内的PTX浓度也较低。用二甲双胍/LKB1处理后，SLCO1B3表达和细胞内PTX浓度均增加。敲低AMPK可导致SLCO1B3表达降低。此外，体外和体内实验表明，二甲双胍不仅能单独明显抑制A549-PTX肿瘤异种移植和A549-PTX增殖，还能增强PTX对A549-PTX的疗效，这可能与SLCO1B3有关。为了验证这一点，我们用AMPK激活剂和抑制剂处理A549细胞，然后发现AMPK激活剂可削弱PTX抑制SLCO1B3的作用，而其抑制剂则有相反作用。敲低SLCO1B3后，AMPK使A549对紫杉醇重新敏感的作用降低。综上所述，激活AMPK可上调SLCO1B3表达，增强A549细胞对PTX的敏感性，为克服PTX耐药提供了新途径。
