Hyaluronan (HA) is one of the major components of the extracellular matrix. Several solid tumors produce high levels of HA, which promotes survival and multidrug resistance (MDR). HA oligomers (oHAs) can block HA effects. However, little is known about the role of HA in hematological malignancies. The aim of this work was to determine whether HA or its oligomers can modulate the proliferation of leukemia cells as well as their effect on MDR. Receptors and signaling pathways involved were also analyzed. For this purpose, the human leukemic cell lines K562 and Kv562, which are sensitive and resistant to Vincristine (VCR), respectively, were used. We demonstrated that HA induced cell proliferation in both cell lines. On K562 cells, this effect was mediated by cluster differentiation 44 (CD44) and activation of both phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) and mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways, whereas on Kv562 cells, the effect was mediated by receptor for hyaluronan-mediated motility (RHAMM) and PI3K/Akt activation. The inhibition of HA synthesis by 4-methylumbelliferone (4MU) decreased cell line proliferation and sensitized Kv562 to the effect of VCR through P-glycoprotein (Pgp) inhibition, in both cases with senescence induction. Moreover, oHAs inhibited K562 proliferation mediated by CD44 as well as Akt and ERK down-regulation. Furthermore, oHAs sensitized Kv562 cells to VCR by Pgp inhibition inducing senescence. We postulate that the synthesis of HA would promote leukemia progression mediated by the triggering of the above-mentioned proliferative signals. These findings highlight the potential use of oHAs and 4MU as coadjuvant for drug-resistant leukemia.

Aims: Heme oxygenase-1 (HO-1) is an enzyme involved in cellular responses to oxidative stress and has also been shown to regulate processes related to cancer progression. In this regard, HO-1 has been shown to display a dual effect with either antitumor or protumor activity, which is also true for breast cancer (BC). In this work, we address this discrepancy regarding the role of HO-1 in BC. Results: HO-1 was detected in human BC tissues, and its protein levels correlated with reduced tumor size and longer overall survival time of patients, thus suggesting the clinical importance of HO-1 in this type of cancer. Contrariwise, nuclear localization of HO-1 correlated with higher tumor grade suggesting that the effect of HO-1 is dependent on its cellular localization. In vivo experiments showed that both pharmacological activation and genetic overexpression of HO-1 reduce the tumor burden in two different animal models of BC. Furthermore, the pharmacological and genetic activation of HO-1 in several BC cell lines reduce the cellular viability by inducing apoptosis and cell cycle arrest and decrease the cellular migration and invasion rates by modulating pathways involved in the epithelial-mesenchymal transition. Furthermore, HO-1 activation impaired in vivo the metastatic dissemination. Innovation and Conclusion: By using various BC cell lines and animal models as well as human tumor samples, we demonstrated that total HO-1 displays antitumor activities in BC. Furthermore, our study suggests that HO-1 subcellular localization may explain the differential effects observed for the protein in different tumor types.

Heme Oxygenase-1 (HO-1) is a type II detoxifying enzyme that catalyzes the rate-limiting step in heme degradation leading to the formation of equimolar quantities of carbon monoxide (CO), free iron and biliverdin. HO-1 was originally shown to localize at the smooth endoplasmic reticulum membrane (sER), although increasing evidence demonstrates that the protein translocates to other subcellular compartments including the nucleus. The nuclear translocation occurs after proteolytic cleavage by proteases including signal peptide peptidase and some cysteine proteases. In addition, nuclear translocation has been demonstrated to be involved in several cellular processes leading to cancer progression, including induction of resistance to therapy and enhanced metastatic activity. In this review, we focus on nuclear HO-1 implication in pathophysiological conditions with special emphasis on malignant processes. We provide a brief background on the current understanding of the mechanisms underlying how HO-1 leaves the sER membrane and migrates to the nucleus, the circumstances under which it does so and, maybe the most important and unknown aspect, what the function of HO-1 in the nucleus is.