Tumor-Induced Oxidative Stress Perturbs Nuclear Factor-κB Activity-Augmenting Tumor Necrosis Factor-α–Mediated T-Cell Death: Protection by Curcumin

Abstract

Cancer patients often exhibit loss of proper cell-mediated immunity and reduced effector T-cell population in the circulation. Thymus is a major site of T-cell maturation, and tumors induce thymic atrophy to evade cellular immune response. Here, we report severe thymic hypocellularity along with decreased thymic integrity in tumor bearer. In an effort to delineate the mechanisms behind such thymic atrophy, we observed that tumor-induced oxidative stress played a critical role, as it perturbed nuclear factor-KB (NF-KB) activity. Tumor-induced oxidative stress increased cytosolic IKBA retention and inhibited NF-KB nuclear translocation in thymic T cells. These NF-KB-perturbed cells became vulnerable to tumor-secreted tumor necrosis factor (TNF)-A (TNF-A)-mediated apoptosis through the activation of TNF receptorassociated protein death domain-associated Fas-associated protein death domain and caspase-8. Interestingly, TNF-Adepleted tumor supernatants, either by antibody neutralization or by TNF-A-small interfering RNA transfection of tumor cells, were unable to kill T cell effectively. When T cells were overexpressed with NF-KB, the cells became resistant to tumor-induced apoptosis. In contrast, when degradationdefective IKBA (IKBA super-repressor) was introduced into T cells, the cells became more vulnerable, indicating that inhibition of NF-KB is the reason behind such tumor/TNF-Amediated apoptosis. Curcumin could prevent tumor-induced thymic atrophy by restoring the activity of NF-KB. Further investigations suggest that neutralization of tumor-induced oxidative stress and restoration of NF-KB activity along with the reeducation of the TNF-A signaling pathway can be the mechanism behind curcumin-mediated thymic protection. Thus, our results suggest that unlike many other anticancer agents, curcumin is not only devoid of immunosuppressive effects but also acts as immunorestorer in tumor-bearing host.

Curcumin reverses T cell-mediated adaptive immune dysfunctions in tumor-bearing hosts

“…Previously, we have shown that curcumin can induce tumor-cell killing, lower systemic toxicity and neutralize oxidative stress in the immune system, resulting in Tcell protection. [28][29][30] Here we report that curcumin reduced the levels of TGF-b and IL-10 in Treg cells and reduced the number of Treg cells in the tumor-bearing hosts. Complex interactions between various signals produced by the tumor and by curcumin ultimately result in augmentation of Th1/Tc1-type responses in the tumor-bearing host.…”

“…We recently demonstrated that curcumin reduced the overall systemic toxicity, while effectively lowering the tumor burden, and prevented tumor-induced T-cell depletion. [28][29][30] This is the first time we are reporting the intricate mechanism of curcumin-induced immune restoration in tumor-bearing animals, and our results suggest that curcumin can prevent tumorinduced immunosuppression via restoration of effector T-cell populations, normalization of the cytokine profile and downregulation of Treg cell activity.…”

“…Cells ware maintained in complete RPMI 1640 medium at 37 uC in humidified incubator containing 5% CO 2 . 29,30 TILs from ascites carcinoma were isolated by positive selection using anti-CD3-coated microbeads. EAC cells were incubated for 48 h in the presence or absence of 10 mM curcumin; supernatant was freed from cellular components and used in a 1 : 1 ratio with RPMI 1640 media to study the effect of tumor supernatant on T cells.…”

Acute Thymic Involution and Mechanisms for Recovery

“…Similarly, curcumin has shown numerous therapeutic characteristics (Srivastava et al 2011). This chemical improves the immune reconstitution during carcinogenesis (Bhattacharyya et al 2007(Bhattacharyya et al , 2010 and prevents deltamethrin-induced thymocyte apoptosis by arresting the oxidative stress through caspasedependent signaling pathways (Kumar et al 2015). Fibroblast growth factor 21 (FGF21) plays a critical role in the regulation of energy metabolism (Salminen et al 2016) and protects against age-associated thymic involution by increasing the cortical TEC and thymocyte progenitors in mice (Youm et al 2016).…”

Inhibitory effect of curcumin on angiogenesis in ectopic endometrium of rats with experimental endometriosis

“…Curcumin is the main component of turmeric. Studies have found that curcumin can inhibit tumor growth by inhibiting angiogenesis both in vivo and in vitro (11)(12)(13)(14)(15). However, the development of endometriosis and the impact of angiogenesis is rarely reported.…”