Lymphotoxin β receptor mediates caspase-dependent tumor cell apoptosis in vitro and tumor suppression in vivo despite induction of NF-κB activation

Abstract

Ligation of the lymphotoxin β receptor (LTβR) has been shown to induce both tumor growth inhibition and promotion. The functions of LTβR in these two contrasting cellular processes require further study. We demonstrated here that mice deficient in LTβR ligands, LTα, LIGHT or both LTβ and LIGHT, exhibit greater susceptibility to methylcholanthrene-induced tumor development. LTα, LTβ and LIGHT were expressed in tumor-infiltrating immune cells, and LTβR was expressed on human colon carcinoma and soft tissue sarcoma (STS) cells. Human LTβR agonist monoclonal antibody (mAb) BS-1 induced both growth inhibition and NF-κB activation in human colon carcinoma, mammary carcinoma and STS cells. Interestingly, BS-1 also significantly inhibited growth of doxorubicin-resistant and radiation-resistant human STS cells in vitro. In the molecular mechanism level, we demonstrated that BS-1 induces caspases 8 and 3 activation and cytochrome c release in tumor cells, suggesting that the LTβR mediates apoptosis at least partially through a caspase-dependent mechanism. Furthermore, mouse LTβR mAb ACH6 suppressed colon carcinoma cell metastatic potential in an experimental metastasis mouse model. Although blocking NF-κB activation did not alter tumor cell growth rate and tumor cell response to LTβR mAb-induced growth inhibition in vitro, surprisingly, blocking NF-κB activation significantly enhanced colon carcinoma cell metastatic potential in vivo, suggesting that the LTβR-mediated apoptosis pathway and NF-κB signaling pathway might cooperate to suppress tumor growth in vivo. In summary, our findings determine that LTβR mediates tumor cell apoptosis in colon carcinoma, mammary carcinoma and sarcoma and that LTβR-activated NF-κB potentially functions as a tumor suppressor.

Tegillarca granosa Extract Haishengsu Induces Apoptosis in Human Hepatocellular Carcinoma Cell Line BEL-7402 Via Fas-Signaling Pathways

“…With regard to caspases, a family of aspartate-specific cysteine proteases, it has been reported that the activation of caspase cascade appears to be directly responsible for many agents to induce apoptosis in many types of cancer cells [30,31]. Caspases are classified based on their mode of activation as either initiator or effector caspases.…”

Altered Dermal Fibroblasts in Systemic Sclerosis Display Podoplanin and CD90

“…As such, it is an effective mimic of the normal cell surface ligand and its properties have been described. 37 BS1 was a gift from Biogen (Cambridge, MA). RNA was isolated from these cultures after 24 hours and subjected to either quantitative PCR using TaqMan primers or a custom human gene specific 78 gene Nanostring array effectively as described.…”

The lymphotoxin β receptor is a potential therapeutic target in renal inflammation

“…77 Both antibodies have been extensively analyzed and used previously. 78,79 In situ hybridization for LTb RNA in situ hybridization was performed using the RNAscope 2.0 brown FFPE Assay (Advanced Cell Diagnostic, Hayward, CA) according to the manufacturer's protocol. Slides were mounted using EcoMount mounting medium (BioCare Medical, Berlin, Germany) and analyzed using LEICA SCN400 Slide scanner (Leica Microsystems, Wetzlar, Germany).…”