Hyperthermia-induced Nuclear Translocation of Transcription Factor YB-1 Leads to Enhanced Expression of Multidrug Resistance-related ABC Transporters

Abstract

Genotoxic stress leads to nuclear translocation of the Y-box transcription factor YB-1 and enhanced expression of the multidrug resistance gene MDR1. Because hyperthermia is used for the treatment of colon cancer in combination with chemoradiotherapy, we investigated the influence of hyperthermia on YB-1 activity and the expression of multidrug resistance-related genes. Here we report that hyperthermia causes YB-1 translocation from the cytoplasm into the nucleus of human colon carcinoma cells HCT15 and HCT116. Nuclear translocation of YB-1 was associated with increased MDR1 and MRP1 gene activity, which is reflected in strong efflux pump activity. However, a combination of hyperthermia and drug treatment effectively reduced cell survival of the HCT15 and HCT116 cells. These results demonstrate that activation of MDR1 and MRP1 gene expression and increased efflux pump activity after hyperthermia were insufficient to cause an increase in drug resistance in colon cancer cell lines. The ability of hyperthermia to abrogate drug resistance in the presence of an increase in functional MDR proteins may provide an explanation for the efficacious results seen in the clinic in colon cancer patients treated with a combination of hyperthermia and chemotherapy. Multidrug resistance (MDR)1 of human malignant tumors represents a major cause of cancer chemotherapy failure. The development of the MDR phenotype is often associated with increased expression of certain ATP-binding cassette transporters (ABC transporters) such as P-glycoprotein and MRP1. The multidrug resistance gene (MDR1) encodes P-glycoprotein, which causes classical MDR. In contrast, the MRP1 gene encodes the multidrug resistance-related protein (MRP1), which is associated with an atypical non-P-glycoprotein-dependent MDR phenotype (1). Although both transporter proteins function as drug-efflux pumps, they share only 15% amino acid homology, transport a non-identical spectrum of anticancer substrates, and show a different distribution in human normal and cancer tissues (2, 3).Colorectal tumors are one of the most prevalent human malignancies and are highly drug resistant because of an MDR phenotype. Intrinsic expression of the ABC transporters Pglycoprotein and MRP1 in colon cancer has been reported (4 -6). To improve the response of colon cancer to chemotherapy, other treatment modalities such as radiation and hyperthermia when used in combination with chemotherapy may be able to increase the efficacy of cancer chemotherapy (7). However, environmental stresses such as drugs, radiation, and hyperthermia harbor the potential to induce or to enhance the MDR phenotype. Induction of MDR1 gene expression by exposure to drugs (8 -10) or radiation (11) were described earlier. In contrast, the influence of hyperthermia on the expression of MDR genes has not been clearly established. Two groups reported a heat-induced elevation of MDR1 gene expression, either observed following a single treatment or after repeated treatments with heat (12, 13). Induction of MRP1 expressi...

Invited Review: Effects of heat and cold stress on mammalian gene expression

“…This has been shown to activate transcription in some experimental systems. For example, in a colon cancer cell line, heat shock produced translocation of Y-box transcription factor 1 from the cytoplasm to the nucleus, leading to increased expression of multidrug resistance transporters MDR-1 and MRP-1 (103).…”

Some p53-binding proteins that can function as arbiters of life and death

“…Nuclear translocation of YB1 occurs in response to a variety of stresses that include UV exposure, DNA-damaging agents, and hypothermia. [37][38][39] Recent evidence suggests that YB1 must first be cleaved, and that only the N-terminal portion translocates to the nucleus. 40 This issue is discussed further below.…”

Akt-dependent nuclear localization of Y-box-binding protein 1 in acquisition of malignant characteristics by human ovarian cancer cells

“…The nuclear localization of YB-1 is required for transcription and DNA repair in response to various environmental stimuli, such as adenovirus infection (Holm et al, 2002), DNA-damaging agents, UV irradiation, hyperthermia (Stein et al, 2001) and serum stimulation (En-Nia et al, 2005). However, as a nucleocytoplasmic shuttling protein, it is important to understand which signalling molecules are involved in the translocation of YB-1 into the nucleus.…”