Jang Te-Hsuan, Lin Sheng-Chieh, Yang Ya-Yu, Lay Jong-Ding, Chang Chih-Ling, Yao Chih-Jung, Huang Jhy-Shrian, Chuang Shuang-En
National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan.
Department of Nursing, National Taichung University of Science and Technology, Taichung 40343, Taiwan.
Cancers (Basel). 2024 Jul 1;16(13):2428. doi: 10.3390/cancers16132428.
Chemotherapy remains a cornerstone in lung cancer treatment, yet emerging evidence suggests that sublethal low doses may inadvertently enhance the malignancy. This study investigates the paradoxical effects of sublethal low-dose chemotherapy on non-small-cell lung cancer (NSCLC) cells, emphasizing the role of Aldo-keto reductase family 1 member B10 (AKR1B10). We found that sublethal doses of chemotherapy unexpectedly increased cancer cell migration approximately 2-fold and invasion approximately threefold, potentially promoting metastasis. Our analysis revealed a significant upregulation of AKR1B10 in response to taxol and doxorubicin treatment, correlating with poor survival rates in lung cancer patients. Furthermore, silencing AKR1B10 resulted in a 1-2-fold reduction in cell proliferation and a 2-3-fold reduction in colony formation and migration while increasing chemotherapy sensitivity. In contrast, the overexpression of AKR1B10 stimulated growth rate by approximately 2-fold via ERK pathway activation, underscoring its potential as a target for therapeutic intervention. The reversal of these effects upon the application of an ERK-specific inhibitor further validates the significance of the ERK pathway in AKR1B10-mediated chemoresistance. In conclusion, our findings significantly contribute to the understanding of chemotherapy-induced adaptations in lung cancer cells. The elevated AKR1B10 expression following sublethal chemotherapy presents a novel molecular mechanism contributing to the development of chemoresistance. It highlights the need for strategic approaches in chemotherapy administration to circumvent the inadvertent enhancement of cancer aggressiveness. This study positions AKR1B10 as a potential therapeutic target, offering a new avenue to improve lung cancer treatment outcomes by mitigating the adverse effects of sublethal chemotherapy.
化疗仍然是肺癌治疗的基石，但新出现的证据表明，亚致死低剂量化疗可能会无意中增强恶性肿瘤的生长。本研究调查了亚致死低剂量化疗对非小细胞肺癌（NSCLC）细胞的矛盾效应，重点关注醛糖还原酶家族1成员B10（AKR1B10）的作用。我们发现，亚致死剂量的化疗意外地使癌细胞迁移增加了约2倍，侵袭增加了约3倍，这可能促进了转移。我们的分析显示，紫杉醇和阿霉素治疗后AKR1B10显著上调，这与肺癌患者的低生存率相关。此外，沉默AKR1B10导致细胞增殖减少1-2倍，集落形成和迁移减少2-3倍，同时增加了化疗敏感性。相反，AKR1B10的过表达通过激活ERK途径使生长速率提高了约2倍，突出了其作为治疗干预靶点的潜力。应用ERK特异性抑制剂后这些效应的逆转进一步证实了ERK途径在AKR1B10介导的化疗耐药中的重要性。总之，我们的研究结果对理解化疗诱导的肺癌细胞适应性有重要贡献。亚致死化疗后AKR1B10表达升高呈现了一种导致化疗耐药发展的新分子机制。这凸显了在化疗给药中采取策略性方法以避免无意中增强癌症侵袭性的必要性。本研究将AKR1B10定位为潜在的治疗靶点，为通过减轻亚致死化疗的不良反应来改善肺癌治疗效果提供了一条新途径。
