The expression of P-glycoprotein in leukemia cells is associated with the upregulated expression of nestin, a class 6 filament protein.

Multidrug resistance (MDR) is a serious obstacle to the effective chemotherapeutic treatment of leukemia. Expression of plasma membrane P-glycoprotein (P-gp), a transporter involved in drug efflux, is the most frequently observed molecular causality of MDR. We observed the coexpression of P-gp and the filament protein nestin in the acute myeloid leukemia (AML) cell lines SKM-1 and MOLM-13 following the induction of P-gp expression using vincristine. Nestin is considered a marker of neural stem cells and neural progenitor cells. The aim of this study was to determine whether there is causal relationship between the expression of P-glycoprotein and the expression of nestin in both of these AML cell lines. The expression of P-gp was induced in SKM-1 cells by selective pressure using vincristine (VCR), mitoxantrone (MTX), azacytidine (AzaC) and lenalidomide (LEN). Whereas the selective pressure of VCR, MTX and AzaC also induced P-gp expression in MOLM-13 cells, LEN was found to be ineffective in this regard. In all cases in which P-gp expression was induced in SKM-1 and MOLM-13 cells, its expression was associated with the induction of nestin mRNA expression and the presence of a 200-220kDa nestin-immunoreactive protein band in western blots. Silencing P-gp expression using s10418 siRNA (known as the P-gp silencer) was associated with the downregulation of the nestin transcript level, demonstrated using RT-PCR. Nestin mRNA was also observed in two P-gp-positive variants of L1210 cells that were obtained either by selection with VCR or by transfection with a retrovirus encoding human P-gp. Detectable levels of nestin transcripts were not observed in P-gp-negative parental L1210 cells. Taken together, these results indicated that the induction of P-gp expression is causally associated with the expression of nestin in leukemia cells.

Vincristine-induced expression of P-glycoprotein in MOLM-13 and SKM-1 acute myeloid leukemia cell lines is associated with coexpression of nestin transcript.

Nestin is a class 6 filament protein typically expressed in neural stem/progenitor cells. However, nestin expression has been observed in other tissues during mammalian embryogenesis. In human neural stem/progenitor cells, coexpression of nestin and P-glycoprotein (P-gp, ABCB1 member of the ABC transporter family) was detected. P-gp-mediated drug efflux is the most common molecular cause of multidrug resistance in neoplastic cells. Nestin expression has also been detected in various human solid tumours as well as in the corresponding established cell lines. Interestingly, expression of nestin in different leukemia cells has been recently reported. Here, we show that expression of P-gp is associated with the simultaneous expression of nestin in acute myeloid leukemia cell lines (MOLM-13 and SKM-1) under the selective pressure of vincristine, a substance that may induce P-gp expression in neoplastic cells.