1. <scp>l</scp> ‐lactic acidosis confers insensitivity to PKC inhibitors by competing for uptake via monocarboxylate transporters
- Author
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Chia-Hung Chen, You-Chi Liu, Jhih-Yi Chiou, Wei Chien Huang, Chih Yen Tu, Chao-Jung Chen, Khuong T L Nguyen, Yi-Cheng Shen, Fang-Ju Cheng, and Chih-Hsin Tang
- Subjects
Monocarboxylic Acid Transporters ,Lung Neoplasms ,Physiology ,Clinical Biochemistry ,GPR81 ,Pharmacology ,Carcinoma, Non-Small-Cell Lung ,Tumor Microenvironment ,medicine ,Humans ,Lactic Acid ,Epidermal growth factor receptor ,Receptor ,Protein Kinase Inhibitors ,Protein kinase C ,Monocarboxylate transporter ,Tumor microenvironment ,Symporters ,biology ,Chemistry ,Cell Biology ,medicine.disease ,ErbB Receptors ,Lactic acidosis ,biology.protein ,Acidosis, Lactic ,Tyrosine kinase - Abstract
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.
- Published
- 2021