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.
化疗仍是肺癌治疗的基石，然而新出现的证据表明，亚致死性低剂量化疗可能无意中增强肿瘤恶性程度。本研究探讨了亚致死性低剂量化疗对非小细胞肺癌细胞的矛盾效应，重点关注醛酮还原酶家族1成员B10的作用机制。研究发现，亚致死剂量化疗意外地使癌细胞迁移能力提升约2倍，侵袭能力增强约3倍，可能促进转移进程。分析显示，紫杉醇和阿霉素治疗可显著上调AKR1B10表达，且该现象与肺癌患者不良预后密切相关。通过基因沉默技术抑制AKR1B10表达后，细胞增殖能力降低1-2倍，克隆形成与迁移能力减弱2-3倍，同时化疗敏感性显著提升。相反，过表达AKR1B10可通过激活ERK通路使细胞生长速率提升约2倍，这凸显了其作为治疗干预靶点的潜力。应用ERK特异性抑制剂可逆转上述效应，进一步证实ERK通路在AKR1B10介导的化疗耐药中的关键作用。本研究深化了对肺癌细胞化疗适应性机制的理解，揭示亚致死化疗后AKR1B10表达上调是导致化疗耐药的新分子机制，强调需要制定更精准的化疗策略以避免意外增强肿瘤侵袭性。AKR1B10作为潜在治疗靶点，为通过减轻亚致死化疗不良反应改善肺癌治疗效果提供了新途径。
The Role of AKR1B10 in Lung Cancer Malignancy Induced by Sublethal Doses of Chemotherapeutic Drugs
肿瘤(癌症)患者之家