Abstract
Senescence, an inherent tumor suppressive mechanism, is a critical determinant for chemotherapy. 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. 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. 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. Senescence-associated DNA damage was also evident from the increase in promyelocytic leukemia bodies, γH2AX foci, and SAHF. Conversely, overexpression of MCT2 prevented doxorubicin-induced ROS accumulation (P = 0.0002) and cell growth inhibition (P = 0.001). MCT2 knockdown suppressed KRAS mutant colorectal tumor growth in vivo. In addition, MCT2 knockdown and cytostatic drug combination further enhanced the antitumor effect. These findings support the use of MCT2 as a promising target for inhibition of colorectal cancer.
Highlights
Tumors are usually limited in terms of oxygen availability [1] and adapt to hypoxia by uncoupling their glycolytic metabolism from aerobic respiration [2]
Our results showed that increased levels of reactive oxygen species (ROS) mainly mediate monocarboxylate transporter 2 (MCT2) knockdown, causing an increase in mitochondrial dysfunction and senescence-associated nuclear markers, including promyelocytic leukemia (PML) bodies, gH2AX, and SAHF [10]
To establish whether MCT2 is directly involved in drug-induced senescence of colorectal cancer cells, we further examined the effects of MCT2 knockdown using specific siRNA
Summary
Tumors are usually limited in terms of oxygen availability [1] and adapt to hypoxia by uncoupling their glycolytic metabolism from aerobic respiration [2]. Lactic acid released by glucose-consuming hypoxic tumors [2] is consumed as a predominant source of oxidative metabolism of tumor cells [3] The gatekeepers of this metabolic process are monocarboxylate transporters (MCT; MCT1, 2, 3, and 4), which transport monocarboxylates, including pyruvate and lactate [4]. The effects and precise mechanisms of MCT2 inhibition in colorectal cancer remain unknown at present. We investigated the effects of MCT2 knockdown in regulating 5-FU sensitivity of colorectal cancer. We investigated the effects of MCT2 knockdown alone or in combination with 5-FU on human colorectal cancer xenografted in mice. The selective expression of MCT2 (but not MCT1) protein in human primary colorectal tumors, but not normal tissues, further suggests that targeting MCT2 represents a promising strategy to enhance therapeutic efficacy
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