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  • 6-diazo-5-oxo-L-nor-Leucine Corresponding author at Department of Biochemistry School

    2022-05-09

    Corresponding author at: Department of Biochemistry, School of Medicine, University of Buenos Aires, Paraguay 2155 5th floor, CABA C1121ABG, Argentina.
    E-mail address: [email protected] (E.J. Podesta). 1 These authors have contributed equally to this work.
    by human arterial smooth muscle cells [9], the regulation of axonal transport of synaptic vesicles in Drosophila melanogaster [10], ferrop-tosis-mediated production of 5-hydroxyeicosatetraenoic 6-diazo-5-oxo-L-nor-Leucine [11] and zebrafish embryogenesis [12].
    In pathological processes, the ACSL4 gene has been found to be deleted in a family with Alport syndrome, elliptocytosis, and mental retardation [13]. ACSL4 has been linked to ferroptosis-associated dis-ease [14] and adipocyte dysfunction and obesity [15]. ACSL4 associa-tion with cancer has been inferred from abnormal expression in colon, breast, prostate and hepatocellular carcinoma., and its high expression has been found to correlate with triple-negative breast cancers [16–19] and tumor cell aggressiveness in different types of cancer [19–22], particularly metastatic breast cancer (MBC) [18–21,23].
    Breast cancer constitutes a heterogeneous group of diseases which vary in morphology, biology and response to therapy, and represents the second most important cause of death by cancer among women worldwide.
    In particular, MBC – a type of breast cancer in which cells have migrated and invaded other organs such as lung and bone – is generally regarded as incurable, with response rates and duration progressively declining with subsequent lines of treatment [24,25]. MBC has a het-erogeneous etiology, including triple-negative breast cancer, and is one of the most frequent causes of death by cancer, with more than 500,000 annual deaths worldwide [26].
    The treatment of disseminated cancer is usually faced with obstacles associated to therapy resistance [27]. Research into the mechanisms by which cancer eludes treatment has begun to yield a wealth of in-formation on the reasons for therapy failure and valuable findings on how to circumvent drug resistance in cancer cells [28]. As resistance to anti-cancer drug treatment stems from a wide range of factors including individual variations in patients and somatic cell genetic differences even in tumors with a common tissue of origin, these studies also aim to design agents which may bypass the usual means of resistance with a view to more satisfactory therapy results [28].
    Although frequently intrinsic to cancer, cancer cell resistance may also be acquired over the course of therapy. Resistance acquisition may respond to the expression of one or more energy-dependent transporters which eject anti-cancer drugs from cells, or may result from hormonal resistance, insensitivity to drug-induced apoptosis and induction of drug-detoxification [29,30]. Therefore, the design of fully effective anti-cancer drugs requires a better understanding of tumor biology and the molecular mechanisms of resistance.
    Regarding functional aspects, our group and others have found ACSL4 to be involved in the mechanism underlying increased breast cancer cell proliferation, invasion and migration, both in vitro and in vivo [18,19,21,23]. Sole ACSL4 cDNA transfection in non-aggressive breast cancer cells MCF-7, which do not develop tumor in mice in ab-sence of estrogen, renders a highly aggressive phenotype. Furthermore, the injection of these ACSL4-transfected MCF-7 cells in nude mice triggers tumor growth, tumors with nuclear polymorphism, high mi-totic levels and low expression of estrogen and progesterone receptors [21].
    In an attempt to unveil the early steps through which ACSL4 in-creases tumor growth and progression, our group has recently de-monstrated a key role for ACSL4 expression in cancer cell biology, regulating genes and signal transduction mechanisms underlying pro-liferation, migration and invasion [31]. In addition, we have shown the participation of ACSL4 in tumor resistance to hormone therapy [20]. In this context, we hypothesize that ACSL4 may be implicated in tumor resistance to chemotherapeutic therapy through the action of ABC transporters, and that its downregulation or inhibition in triple-nega-tive breast cancer cells may thus pave the way for future effective therapeutic approaches.