Prothymosin alpha: a ubiquitous polypeptide with potential use in cancer diagnosis and therapy

Abstract

The thymus is a central lymphoid organ with crucial role in generating T cells and maintaining homeostasis of the immune system. More than 30 peptides, initially referred to as "thymic hormones," are produced by this gland. Although the majority of them have not been proven to be thymus-specific, thymic peptides comprise an effective group of regulators, mediating important immune functions. Thymosin fraction five (TFV) was the first thymic extract shown to stimulate lymphocyte proliferation and differentiation. Subsequent fractionation of TFV led to the isolation and characterization of a series of immunoactive peptides/polypeptides, members of the thymosin family. Extensive research on prothymosin α (proTα) and thymosin α1 (Tα1) showed that they are of clinical significance and potential medical use. They may serve as molecular markers for cancer prognosis and/or as therapeutic agents for treating immunodeficiencies, autoimmune diseases and malignancies. Although the molecular mechanisms underlying their effect are yet not fully elucidated, proTα and Tα1 could be considered as candidates for cancer immunotherapy. In this review, we will focus in principle on the eventual clinical utility of proTα, both as a tumor biomarker and in triggering anticancer immune responses. Considering the experience acquired via the use of Tα1 to treat cancer patients, we will also discuss potential approaches for the future introduction of proTα into the clinical setting.

Ovarian malignant ascites-derived lymphocytes stimulated with prothymosin α or its immunoactive decapeptide lyse autologous tumour cells in vitro and retard tumour growth in SCID mice

“…An anticipated scenario, sustained by previous data from us, 13,18,20,21 and others, 14,19 and the results presented herein, stands in the lately elucidated adjuvant mode of action of the peptides: proTa and proTa(100-109) ligate TLRs (TLR-4 and possibly others) on antigen presenting cells (APCs; mo/mu, DCs) present in ascites-derived TALs, and induce their maturation. Immunocompetent APCs, subsequently shift their immunosuppressive secretion profile towards a suitable pro-inflammatory cytokine (including type I IFNs) pattern.…”

“…15 In view of the role of proTa and proTa(100-109) in stimulating monocytes and DCs and, downstream thereof, T-cell functions, 13,[18][19][20] we assessed the effect of these peptides in enhancing the cytotoxicity of ovarian cancer patients' TALs. Ascitic fluids contain both mo/mu and DCs.…”

“…12 In view of alternative strategies aiming to improve the impaired TAL functions, we assessed the effect of the immunomodulator prothymosin alpha (proTa), a 109-residue long polypeptide, with established immunoenhancing role. 13 In vitro and in vivo studies showed that proTa increases the expression of major histocompatibility complex (MHC) class II on human monocytes, murine splenocytes and tumour cell lines. 14 In peripheral blood mononuclear cells (PBMCs) from patients with breast, lung and ovarian cancer, proTa increased the cytotoxicity of CTLs against autologous tumour cells.…”

Thymosin alpha 1 suppresses proliferation and induces apoptosis in breast cancer cells through PTEN-mediated inhibition of PI3K/Akt/mTOR signaling pathway

“…Thus, thymosin alpha 1, an immunoactive peptide, has been suggested as a candidate molecule for cancer immunotherapy [13]. Ta1 may serve as a therapeutic agent for treating immunodeficiencies and autoimmune diseases [14].…”

Prothymosin α and a prothymosin α-derived peptide enhance TH1-type immune responses against defined HER-2/neu epitopes

“…Released from dead cells, extracellular proTα acquires multi-functional immunomodulatory properties [18]. We and others have previously shown that proTα upregulates the expression of IRAK-4 in human monocytes [19], ligates TLR-4 on murine macrophages and signals through MyD88-dependent and independent pathways [20].…”