Targeting protein kinase C (PKC) family was found to repress the migration and resistance of non-small cell lung cancer cells to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, none of the PKC inhibitors has been approved for anticancer therapy yet due to the limited efficacy in clinical trials, and the underlying mechanisms remain unclear. l-lactic acidosis, a common condition comprising high l-lactate concentration and acidic pH in the tumor microenvironment, has been known to induce tumor metastasis and drug resistance. In this study, l-lactic acid was found to reverse the inhibitory effects of pan-PKC inhibitors GO6983 on PKC activity, cell migration, and EGFR-TKI resistance, but these effects were not affected by the modulators of lactate receptor GPR81. Interestingly, blockade of lactate transporters, monocarboxylate transporter-1 and -4 (MCT1 and MCT4), attenuated the intracellular level of GO6983, and its inhibitory effect on PKC activity, suggesting that lactic acid promotes the resistance to PKC inhibitors by competing for the uptake through these transporters rather than by activating its receptor, GPR81. Our findings explain the underlying mechanisms of the limited response of PKC inhibitors in clinical trials.

中文翻译：

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L-乳酸酸中毒通过单羧酸转运蛋白竞争摄取而对 PKC 抑制剂不敏感

发现靶向蛋白激酶 C (PKC) 家族可抑制非小细胞肺癌细胞对表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂 (TKI) 的迁移和耐药性。然而，由于在临床试验中疗效有限，目前还没有一种 PKC 抑制剂被批准用于抗癌治疗，其潜在机制仍不清楚。l-乳酸酸中毒是一种常见的疾病，包括肿瘤微环境中的高l-乳酸浓度和酸性 pH 值，已知会诱导肿瘤转移和耐药性。在这项研究中，升发现-乳酸可逆转泛 PKC 抑制剂 GO6983 对 PKC 活性、细胞迁移和 EGFR-TKI 抗性的抑制作用，但这些作用不受乳酸受体 GPR81 调节剂的影响。有趣的是，乳酸转运蛋白单羧酸转运蛋白-1和-4（MCT1和MCT4）的阻断减弱了GO6983的细胞内水平及其对PKC活性的抑制作用，表明乳酸通过竞争摄取来促进对PKC抑制剂的抗性通过这些转运蛋白而不是通过激活其受体 GPR81。我们的研究结果解释了 PKC 抑制剂在临床试验中反应有限的潜在机制。