Release of macrophage migration inhibitory factor by neuroendocrine-differentiated LNCaP cells sustains the proliferation and survival of prostate cancer cells

Abstract

The acquisition of neuroendocrine (NE) characteristics by prostate cancer (PCa) cells is closely related to tumour progression and hormone resistance. The mechanisms by which NE cells influence PCa growth and progression are not fully understood. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine involved in oncogenic processes, and MIF serum levels correlate with aggressiveness of PCa. Here, we investigated the regulation and the functional consequences of MIF expression during NE transdifferentiation of PCa cells. NE differentiation (NED) of LNCaP cells, initiated either by increasing intracellular levels of cAMP or by culturing cells in an androgen-depleted medium, was associated with markedly increased MIF release. Yet, intracellular MIF protein and mRNA levels and MIF gene promoter activity decreased during NED of LNCaP cells, suggesting that NED favours MIF release despite decreasing MIF synthesis. Adenoviral-mediated forced MIF expression in NE-differentiated LNCaP cells increased cell proliferation without affecting the expression of NE markers. Addition of exogenous recombinant MIF to LNCaP and PC-3 cells stimulated the AKT and ERK1/2 signalling pathways, the expression of genes involved in PCa, as well as proliferation and resistance to paclitaxel and thapsigargin-induced apoptosis. Altogether, these data provide evidence that increased MIF release during NED in PCa may facilitate cancer progression or recurrence, especially following androgen deprivation. Thus, MIF could represent an attractive target for PCa therapy.

Prognostic Value of the Pretreatment Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio for Patients with Neuroendocrine Tumors: An Izmir Oncology Group Study

“…The belief that an immune response opposes NETs is also substantiated by the frequent finding of lymphocyte infiltration of NETs, as assessed by immunohistochemistry for CD3 (a general T lymphocyte marker), CD4, CD8 and CD56 [22,23,24,25]. Other studies have also been conducted on the immune system [26,27,28]. Immunotherapies are now being used clinically to inhibit several immune cell subsets that promote tumor development [29].…”

Neuroendocrine differentiation in prostate cancer: Novel morphological insights and future therapeutic perspectives

“…As for macrophage migration inhibitory factor (MIF), it is a pro-inflammatory cytokine involved in prostate carcinogenesis. In vitro studies reported that NE differentiation of LNCaP cells is associated with markedly increased MIF release, which promotes the proliferation of PCa cells through the stimulation of the AKT and ERK1/2 signaling pathways [20].…”

Hallmarks of gastrointestinal neuroendocrine tumours: implications for treatment

“…Results from a study comparing pNET patients and healthy unrelated controls indicated an association between the high-expression C/T-511 IL1b (IL1B) genotype and susceptibility to pNETs (Cigrovski Berkovic et al 2012). Interestingly, macrophage migration inhibitory factor (MIF) has been recently linked to neuroendocrine differentiation in prostate cancer (Tawadros et al 2013). Immunotherapies are now being used clinically to inhibit several immune cell subsets that promote tumour development (Coussens et al 2013).…”