ApoB-lipoproteins and their components modulate intracellular metabolism and have been associated with the development of neoplastic phenomena, such as proliferation, anchorage-independent growth, epithelial-mesenchymal transition, and cancer invasion. In cancer cells, the modulation of targets that regulate cholesterol metabolism, such as synthesis de novo, endocytosis, and oxidation, are contributing factors to cancer development. While mechanisms associated with sterol regulatory element-binding protein 2 (SREBP-2)/mevalonate, the low-density lipoprotein receptor (LDL-R) and liver X receptor (LXR) have been linked with tumor growth; metabolites derived from cholesterol-oxidation, such as oxysterols and epoxy-cholesterols, also have been described as tumor processes-inducers. From this notion, we perform an analysis of the role of lipoproteins, their association with intracellular cholesterol metabolism, and the impact of these conditions on breast cancer development, mechanisms that can be shared during atherogenesis promoted mainly by LDL. Pathways connecting plasma dyslipidemias in conjunction with the effect of cholesterol-derived metabolites on intracellular mechanisms and cellular plasticity phenomena could provide new approaches to elucidate the triggering factors of carcinogenesis, conditions that could be considered in the development of new therapeutic approaches.
Cells employ several adaptive mechanisms under conditions of accelerated cell division, such as the unfolded protein response (UPR). The UPR is composed of a tripartite signaling system that involves ATF6, PERK, and IRE1, which maintain protein homeostasis (proteostasis). However, deregulation of protein translation initiation could be associated with breast cancer (BC) chemoresistance. Specifically, eukaryotic initiation factor-4A (eIF4A) is involved in the unfolding of the secondary structures of several mRNAs at the 5′ untranslated region (5′-UTR), as well as in the regulation of targets involved in chemoresistance. Importantly, the tumor suppressor gene PDCD4 could modulate this process. This regulation might be disrupted in chemoresistant triple negative-BC (TNBC) cells. Therefore, we characterized the effect of doxorubicin (Dox), a commonly used anthracycline medication, on human breast carcinoma MDA-MB-231 cells. Here, we generated and characterized models of Dox chemoresistance, and chemoresistant cells exhibited lower Dox internalization levels followed by alteration of the IRE1 and PERK arms of the UPR and triggering of the antioxidant Nrf2 axis. Critically, chemoresistant cells exhibited PDCD4 downregulation, which coincided with a reduction in eIF4A interaction, suggesting a sophisticated regulation of protein translation. Likewise, Dox-induced chemoresistance was associated with alterations in cellular migration and invasion, which are key cancer hallmarks, coupled with changes in focal adhesion kinase (FAK) activation and secretion of matrix metalloproteinase-9 (MMP-9). Moreover, eIF4A knockdown via siRNA and its overexpression in chemoresistant cells suggested that eIF4A regulates FAK. Pro-atherogenic low-density lipoproteins (LDL) promoted cellular invasion in parental and chemoresistant cells in an MMP-9-dependent manner. Moreover, Dox only inhibited parental cell invasion. Significantly, chemoresistance was modulated by cryptotanshinone (Cry), a natural terpene purified from the roots of Salvia brandegeei. Cry and Dox co-exposure induced chemosensitization, connected with the Cry effect on eIF4A interaction. We further demonstrated the Cry binding capability on eIF4A and in silico assays suggest Cry inhibition on the RNA-processing domain. Therefore, strategic disruption of protein translation initiation is a druggable pathway by natural compounds during chemoresistance in TNBC. However, plasmatic LDL levels should be closely monitored throughout treatment.
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