Abstract
Monocarboxylate transporter4 (MCT4) is responsible for the efflux of lactate and high expression of MCT4 is related to poor prognosis in multiple cancers. Herein, Fluvastatin, regarded as a lipid-metabolic regulator, has been screened out as an inhibitor of MCT4 for lung adenocarcinoma (LUAD) treatment. As tumor cell-derived microparticles (TMPs) have advantages in low toxicity, biocompatibility and biological targeting, TMPs serve as a highly efficient drug-delivery system to transport Fluvastatin in a relatively low dosage. TMPs encapsulating Fluvastatin (TMP-F), consistent with antitumor function of Fluvastatin, can impede lactate efflux by inhibiting MCT4 expression, resulting in attenuated LUAD progression. TMP-F provokes reversion of immunosuppressive tumor microenvironment (TME) by appealing to infiltration of NK and CD8+ T cells, polarizing M2-type to M1-type macrophages, and decreasing Treg and myeloid-derived suppressor cells (MDSC). In addition, co-administration of TMP-F and chemotherapy Cisplatin still reinforces the antitumor immune response. Meanwhile, TMP-F improves antitumor efficiency of Cisplatin and curbs lung metastasis. Overall, TMP-F or therapeutic alliance with Cisplatin represents a promising strategy for enhancing therapeutic effect on LUAD.
Introduction
Cancer cells are active in glucose metabolism, especially in aerobic glycolysis, which is well-known for “Warburg effect” [4]. Accordingly, lactate as a kind of disposal of glucose carbon pool is continuously produced. Excess lactate accumulation makes intracellular environment acidified and causes harm to cell viability. Therefore, lactate transportation system works for the sake of homeostasis. During the process of excreting lactate and eliminating protons, monocarboxylate transporters (MCTs) play a dominant part [5]. Within MCTs belonging to the solute carrier 16 (SLC16) family, MCT 1–4 are transmembrane proton dependent transporters and prompt plenty of researches due to its ability to transport products of the glycolysis cycle, involving lactate and pyruvate [6]. Evidence has indicated that MCT1 is ubiquitously expressed in normal tissue, while MCT4 is over-expressed in multiple cancer cells [7]. MCT1 is able to facilitate lactate influx when lactate is used to fuel gluconeogenesis, as well as help lactate efflux in certain glycolytic cells [8]. However, owing to low affinity for pyruvate and relatively high affinity for lactate, MCT4 primarily transports lactate from glycolytic cells to extracellular space [7], [9]. Acidified microenvironment of tumor cells and balanced pH homeostasis, under the help of MCT4 or other transporters, promote invasion and metastasis and also blunt anti-tumor function of immune cells [10], [11]. What’s more, MCT4 is found to correlate with poor prognosis in cancer patients such as hepatocellular carcinoma, prostate cancer, lung cancer and other cancers [12], [13], [14]. For a long time, MCT4 has been aimed at in the field of cancer therapy, and knocking down MCT4 expression in cancers appears satisfactory antitumor effect [15], [16]. Thus, it is meaningful to explore and study potential MCT4 inhibitors for the purpose of suppressing cancer proliferation and modulating tumor microenvironment (TME). In present studies, MCT4 can be inhibited by various pharmacological intervention using VB124, CB-2M, CHC or other small molecules, while these drugs have yet to obtain FDA approval for clinical use and their toxic side effects on human beings need to be verified [12], [17], [18]. Considering that there are plenty of unknowns surrounding biosafety and effectiveness of existing MCT4 inhibitors, we have decided to screen FDA-approved medicine storehouse to look for potential MCT4 inhibitors which are safer to human beings. One of the lipophilic statins: Fluvastatin, possessing monocarboxylate structure, has been screened out. Relatively speaking, Fluvastatin is safe and is widely used in cardiovascular diseases [19], [20]. Hence, we explored the conventional drug in new use and investigated for the first time whether Fluvastatin could be an inhibitor of MCT4 in LUAD cell lines and be significant for LUAD treatment.
