NIH grant HL115557 and UL1 TR000040.

Irreversible growth arrest (also called senescence) has emerged recently as a tumor suppressor mechanism and a key determinant of cancer chemotherapy outcome. Previous work from our laboratory suggested that the cellular ability to undergo or to escape senescence dictates its fate to become drug-sensitive or drug-resistant, respectively. In the present study, we made the hypothesis that longevity genes, by virtue of their ability to inhibit senescence, may contribute to the onset of drug resistance. We report that expression of the longevity gene sirt1 increased both at the RNA and protein levels in all the five drug-resistant cell lines tested when compared with their drug-sensitive counterparts. In addition, biopsies from cancer patients treated with chemotherapeutic agents also expressed high levels of this molecule. These changes were specific for sirt1 because the expression of other members of its family was not affected. More importantly, small interfering RNA-mediated down-regulation of sirt1 significantly reversed the resistance phenotype and reduced expression of the multidrug resistance molecule P-glycoprotein. This was further confirmed by ectopic overexpression of sirt1, which induced expression of P-glycoprotein and rendered cells resistant to doxorubicin. Collectively, these findings uncovered a novel function for the longevity gene sirt1 as a potential target for diagnosis and/or treatment of cancer resistance to chemotherapy. They also describe a proof of principle that signaling pathways implicated in longevity may share similarities with those leading to development of drug resistance in cancer. (Cancer Res 2005; 65(22): 10183-7)

Macrophages play important roles in recycling iron derived from the clearance of red blood cells (RBCs). They are also a critically important component of host defense, protecting against invading pathogens. However, the effects on macrophage biology of acutely ingesting large numbers of RBCs are not completely understood. To investigate this issue, we used a mouse model of RBC transfusion and clearance, which mimics the clinical setting. In this model, transfusions of refrigerator storage-damaged (ie, "old") RBCs led to increased erythrophagocytosis by splenic red pulp macrophages (RPMs). This robust erythrophagocytosis induced ferroptosis, an iron-dependent form of cell death, in RPMs. This was accompanied by increases in reactive oxygen species and lipid peroxidation in vivo, which were reduced by treatment in vitro with ferrostatin-1, a ferroptosis inhibitor. Old RBC transfusions also induced RPM-dependent chemokine expression by splenic Ly6C monocytes, which signaled Ly6C monocyte migration from bone marrow to spleen, where these cells subsequently differentiated into RPMs. The combination of cell division among remaining splenic RPMs, along with the influx of bone marrow-derived Ly6C monocytes, suggests that, following RPM depletion induced by robust erythrophagocytosis, there is a coordinated effort to restore homeostasis of the RPM population by local self-maintenance and contributions from circulating monocytes. In conclusion, these findings may be clinically relevant to pathological conditions that can arise as a result of increased erythrophagocytosis, such as transfusion-related immunomodulation and impaired host immunity.

No abstract

Thyroid hormone has been recently shown to induce tumor growth and angiogenesis via a plasma-membrane hormone receptor on integrin alphaVbeta3. The receptor is at or near the Arg-Gly-Asp (RGD) recognition site on the integrin that is important to extracellular matrix (ECM) protein and vascular growth factor interactions with the integrin. In the present study, we examined the possibility that tetraiodothyroacetic acid (tetrac), a deaminated, non-agonist thyroid hormone analog that binds to the integrin receptor, may modulate vascular growth factor-induced angiogenesis in the absence of thyroid hormone. Angiogenesis models were studied in which VEGF or FGF2 (1-2 microg/ml) induced tube formation in human dermal microvascular endothelial cells (HDMEC), stimulated new blood vessel branch formation in the chick chorioallantoic membrane (CAM) and induced angiogenesis in the mouse matrigel model. In all models, tetrac (1-10 microM) and at 10 microg in mouse matrigel inhibited the pro-angiogenesis activity of VEGF and FGF2 by more than 50%. RT-PCR revealed that tetrac (1-3 microM) decreased abundance of angiopoietin-2 mRNA, but not angiopoietin-1 mRNA, in VEGF-exposed endothelial cells, suggesting that specific angiogenic pathways are targeted by tetrac. Tetrac is a novel, inexpensive small molecule whose anti-angiogenic activity in the present studies is proposed to reflect inhibition, via the integrin RGD recognition/thyroid hormone receptor site, of crosstalk between plasma-membrane vascular growth factor receptors and integrin alphaVbeta3.