The Mitochondrial Uncoupling Protein-2 Promotes Chemoresistance in Cancer Cells

Abstract

Cancer cells acquire drug resistance as a result of selection pressure dictated by unfavorable microenvironments. This survival process is facilitated through efficient control of oxidative stress originating from mitochondria that typically initiates programmed cell death. We show this critical adaptive response in cancer cells to be linked to uncoupling protein-2 (UCP2), a mitochondrial suppressor of reactive oxygen species (ROS). UCP2 is present in drug-resistant lines of various cancer cells and in human colon cancer. Overexpression of UCP2 in HCT116 human colon cancer cells inhibits ROS accumulation and apoptosis after exposure to chemotherapeutic agents. Tumor xenografts of UCP2-overexpressing HCT116 cells retain growth in nude mice receiving chemotherapy. Augmented cancer cell survival is accompanied by altered NH 2 -terminal phosphorylation of the pivotal tumor suppressor p53 and induction of the glycolytic phenotype (Warburg effect). These findings link UCP2 with molecular mechanisms of chemoresistance. Targeting UCP2 may be considered a novel treatment strategy for cancer. [Cancer Res 2008;68(8):2813-9]

Mitochondrial Retrograde Signaling Mediated by UCP2 Inhibits Cancer Cell Proliferation and Tumorigenesis

“…48). In leukemia and colon cancer cells, UCP2 overexpression had been reported to have a protumoral effect (49,50). In contrary, in the other tumors derived from cells with very low basal UCP2 expression, including melanoma, UCP2 mRNA expression is decreased (Supplementary Table S4).…”

Protective mitochondrial transfer from bone marrow stromal cells to acute myeloid leukemic cells during chemotherapy

“…[6][7][8][9] Further to this, recent reports demonstrated that different cellular component of the BMME can transfer mitochondria to epithelial cells or solid cancer cell lines through heterocellular contacts. [10][11][12] Although recipient cells displayed an improved metabolism, there is no clear evidence that functional mitochondria are actually transferred.…”

Degradation of an intramitochondrial protein by the cytosolic proteasome

“…UCP2 has a broad distribution and is implicated in a variety of processes, including regulation of reactive oxygen species production (Arsenijevic et al, 2000), food intake (Andrews et al, 2008), insulin secretion (Zhang et al, 2001) and immunity (Arsenijevic et al, 2000) as well as pathologies including atherosclerosis (Blanc et al, 2003), cancer (Derdak et al, 2008), diabetes (Zhang et al, 2001) and neuronal injury (Sullivan et al, 2003). UCP2 levels vary dynamically in response to nutrients and this is achieved by varied expression rates against a background of a very short UCP2 protein half-life of ~1 hour (Rousset et al, 2007;Giardina et al, 2008;Azzu et al, 2008).…”