Abstract
We have previously shown that the epidermal growth factor-receptor (EGFR) tyrosine kinase inhibitor PD153035 induces retinoic acid receptor-β (RAR-β) expression in malignant cells by mechanisms that are independent of its blocking activity on EGFR (ErbB1) or on any other ErbB receptor (ErbB2, ErbB3, ErbB4). RAR-β2, one of three human RAR-β isoforms (RAR-β1, RAR-β2, RAR-β4), is silenced in many tumors and acts as a tumor suppressor. Forced expression of RAR-β2 reverts the malignant phenotype of RAR-β2-negative breast cancer cells and reconstitutes retinoid sensitivity in these cells. Here, we demonstrate that the EGFR inhibitor PD153035 specifically induces RAR-β2, but not the other two isoforms (RAR-β1, RAR-β4) in MDA-MB-468 and MDA-MB-453 human breast cancer cells. Induction was seen at the mRNA (reverse transcription-polymerase chain reaction) and protein level (Western analysis). PD153035-mediated induction of RAR-β2 was associated with synergistic growth inhibition in cells co-treated with PD153035 and all- trans retinoic acid (tRA). Most importantly, PD153035 restored retinoic acid sensitivity in retinoic acid-resistant cells. Our previous work also revealed that PD153035 directly intercalates into the DNA suggesting that changes in the chromatin structure contribute to the RAR-β2-inducing effect of PD153035. This prompted us to examine the effect of DNA intercalating chemotherapeutic drugs such as doxorubicin, amsacrine, and mitoxantrone on the expression of RAR-β. Vincristine was used for comparative reasons, because this drug does not target DNA. All four compounds caused dose-dependent growth inhibition in MDA-MB-468 and MDA-MB-453 cells. Interestingly, compounds that directly interact with the DNA (doxorubicin, amsacrine, mitoxantrone) caused a time-dependent up-regulation of the RAR-β expression in all cell lines examined, whereas the negative control drug vincristine, which causes disruption of microtubule structures, did not stimulate RAR-β expression. These data further support the notion that induction of the RAR-β tumor-suppressor gene in cancer cells by PD153035 is mediated at least in part by its DNA intercalating activity.
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