Michael stone transporter 26/29/2023 ![]() Following informed consent and in accordance with the appropriate Institutional Review Boards, tumor specimens were obtained from patients undergoing surgery at the Samsung Medical Center. Cells were cultured at 37☌ in a humidified 5% CO 2 environment. ![]() Human colon carcinoma (LoVo, HT29, HCT8, HCT116, SW480, and DLD1) and gastric carcinoma (MKN45 and MKN74) cells were grown in RPMI-1640 medium (Gibco Life Science) supplemented with 10% FBS, 1 mmol/L Na 2CO 3, 2 mmol/L L-glutamine, and penicillin-streptomycin. However, earlier analysis of healthy colonic tissues and carcinomas revealed a significant decline in MCT1 protein expression during transition from normality to malignancy ( 9). ![]() Pinheiro and colleagues reported increased expression of MCTs 1, 2, and 4 in colorectal carcinomas ( 8). Therefore, inhibition of MCT1 can retard tumor growth through blocking the energy supply ( 3). Healthy colonocytes derive 60% to 70% of their energy supply from short-chain fatty acids, particularly butyrate, which is transported across the luminal membrane of the colonic epithelium via MCT1. Experimental evidence of the presence of MCT2 in the mitochondrial membrane indicates a role in the mitochondrial import of pyruvate following lactic acid oxidation ( 4). MCT2 displays strong cytoplasmic expression, but no membrane expression in cancer ( 7). MCT1 is present in almost all tissues, whereas MCT2 is expressed in fewer tissue types, suggesting a unique functional role of this protein ( 6). MCT1 and MCT4, but not MCT2, have been shown to interact specifically with CD147, which supports MCT expression on the cell surface. MCT3 is uniquely expressed in the retinal pigment epithelium. MCT2 displays 10-fold higher affinity for monocarboxylates than the MCT1 and MCT4 uptake mechanisms ( 4). The MCT family comprises 14 members, among which only the first 4 (MCT1–4) catalyze the proton-linked transport of metabolically important monocarboxylates, such as lactate, pyruvate, and ketone bodies ( 5). These findings support the use of MCT2 as a promising target for inhibition of colorectal cancer. In addition, MCT2 knockdown and cytostatic drug combination further enhanced the antitumor effect. MCT2 knockdown suppressed KRAS mutant colorectal tumor growth in vivo. Conversely, overexpression of MCT2 prevented doxorubicin-induced ROS accumulation ( P = 0.0002) and cell growth inhibition ( P = 0.001). Senescence-associated DNA damage was also evident from the increase in promyelocytic leukemia bodies, γH2AX foci, and SAHF. Dramatic induction of mitochondrial superoxide generation and decrease in ATP production was observed, indicating that mitochondrial dysfunction is the major mechanism underlying MCT2 knockdown-induced ROS generation. Moreover, the reactive oxygen species (ROS) scavenger, N-acetylcysteine, blocked MCT2 knockdown-induced growth arrest and cellular senescence, indicating a pivotal role of ROS in this pathway. In the present study, we show that the monocarboxylate transporter 2 (MCT2) protein was tumor-selectively expressed in human colorectal malignancies and knockdown of MCT2 induces mitochondrial dysfunction, cell-cycle arrest, and senescence without additional cellular stress in colorectal cancer cell lines. Senescence, an inherent tumor suppressive mechanism, is a critical determinant for chemotherapy.
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