thermore, central obesity with facial fat redistribution, skin changes, as well as depression and cognitive impairment reflect long-term physical and psychological abnormalities in patients with CD, which negatively affect the quality of life [3,7].
Chemoresistance constitutes a major challenge in the treatment of triple-negative breast cancer (TNBC). Mixed-Lineage Kinase 4 (MLK4) is frequently amplified or overexpressed in TNBC where it facilitates the aggressive growth and migratory potential of breast cancer cells. However, the functional role of MLK4 in resistance to chemotherapy has not been investigated so far. Here, we demonstrate that MLK4 promotes TNBC chemoresistance by regulating the pro-survival response to DNA-damaging therapies. We observed that MLK4 knock-down or inhibition sensitized TNBC cell lines to chemotherapeutic agents in vitro. Similarly, MLK4-deficient cells displayed enhanced sensitivity towards doxorubicin treatment in vivo. MLK4 silencing induced persistent DNA damage accumulation and apoptosis in TNBC cells upon treatment with chemotherapeutics. Using phosphoproteomic profiling and reporter assays, we demonstrated that loss of MLK4 reduced phosphorylation of key DNA damage response factors, including ATM and CHK2, and compromised DNA repair via non-homologous end-joining pathway. Moreover, our mRNA-seq analysis revealed that MLK4 is required for DNA damage-induced expression of several NF-кB-associated cytokines, which facilitate TNBC cells survival. Lastly, we found that high MLK4 expression is associated with worse overall survival of TNBC patients receiving anthracycline-based neoadjuvant chemotherapy. Collectively, these results identify a novel function of MLK4 in the regulation of DNA damage response signaling and indicate that inhibition of this kinase could be an effective strategy to overcome TNBC chemoresistance.
Cushing’s disease (CD) is a severe endocrine disorder characterized by chronic hypercortisolaemia secondary to an overproduction of adrenocorticotropic hormone (ACTH) by a pituitary adenoma. Cortisol excess impairs normal glucose homeostasis through many pathophysiological mechanisms. The varying degrees of glucose intolerance, including impaired fasting glucose, impaired glucose tolerance, and Diabetes Mellitus (DM) are commonly observed in patients with CD and contribute to significant morbidity and mortality. Although definitive surgical treatment of ACTH-secreting tumors remains the most effective therapy to control both cortisol levels and glucose metabolism, nearly one-third of patients present with persistent or recurrent disease and require additional treatments. In recent years, several medical therapies demonstrated prominent clinical efficacy in the management of patients with CD for whom surgery was non-curative or for those who are ineligible to undergo surgical treatment. Cortisol-lowering medications may have different effects on glucose metabolism, partially independent of their role in normalizing hypercortisolaemia. The expanding therapeutic landscape offers new opportunities for the tailored therapy of patients with CD who present with glucose intolerance or DM, however, additional clinical studies are needed to determine the optimal management strategies. In this article, we discuss the pathophysiology of impaired glucose metabolism caused by cortisol excess and review the clinical efficacy of medical therapies of CD, with particular emphasis on their effects on glucose homeostasis.
Resistance to chemotherapy leads to high rates of relapse and poor outcomes in patients with triple-negative breast cancer (TNBC). Therefore, there is a need to identify novel molecular targets that could be exploited to overcome TNBC chemoresistance. Mixed-lineage kinase 4 (MLK4) is a member of MLK family of serine/threonine kinases. Large-scale genomic and transcriptomic data indicated that MLK4 gene (MAP3K21/KIAA1804) is amplified and overexpressed in approximately 50% of triple-negative tumors. We have recently demonstrated that MLK4 promotes the aggressive growth and metastatic potential of TNBC cells. However, the functional role of MLK4 in resistance to chemotherapy has not been investigated so far. In our recent study, we have shown that MLK4 contributes to TNBC chemoresistance by regulating the pro-survival response to DNA-damaging therapies. MLK4 knock-down or inhibition sensitized TNBC cell lines to doxorubicin and etoposide in vitro. Moreover, loss of MLK4 enhanced sensitivity of HCC1806 TNBC cell line towards doxorubicin in a xenograft mouse model. Our data indicated that MLK4 silencing induced persistent DNA damage accumulation and enhanced apoptosis in TNBC cells treated with chemotherapeutics. To further determine cellular mechanisms responsible for the identified MLK4-dependent chemoresistance in TNBC, we performed a quantitative phosphoproteomic analysis of control and MLK4-depleted HCC1806 cells, either untreated or treated with doxorubicin. We found that the doxorubicin-induced phosphorylation of several core DNA damage response components, including ATM, TRIM28 (KAP-1), MDC1 and TP53BP1, was impaired in cells with MLK4 knock-down. These findings were further confirmed using HCC1806 cells with CRISPR/Cas9-mediated deletion of MLK4, which showed markedly reduced phosphorylation of ATM kinase at Ser1981 - a site critical for ATM monomerization and activation. ATM was shown to activate NF-κB transcription in response to DNA damage through the well-established nuclear to cytoplasmic signaling pathway involving NEMO. Interestingly, we observed diminished phosphorylation of NEMO and reduced expression of several NF-кB-associated pro-survival cytokines (IL6, IL8, CXCL1, CXCL6) in MLK4-depleted TNBC cells treated with doxorubicin. These data, along with the additional immunoprecipitation and kinase assay experiments, indicate that MLK4 is involved in the regulation of DNA damage response signaling and ATM-NEMO pathway activation. Moreover, our recent results suggest that MLK4 controls autocrine/paracrine signaling loops in cancer cells and tumor microenvironment (TME) upon treatment with chemotherapy. We currently aim to further determine how MLK4-dependent crosstalk between TNBC cells and TME contributes to chemoresistance and tumor progression. Citation Format: Dawid Mehlich, Michal Lomiak, Aleksandra Sobiborowicz, Alicja Mazan, Dagmara Dymerska, Lukasz M. Szewczyk, Anna Mehlich, Agnieszka Borowiec, Monika K. Prelowska, Dominika Nowis, Anna A. Marusiak. Mixed-lineage kinase 4 is involved in the activation of the ATM-NEMO signaling axis in response to DNA damage and confers chemoresistance in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 151.
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