Apoptotic Resistance of Metastatic Tumor Cells in Triple Negative Breast Cancer: Roles of Death Receptor-5

Abstract

Background: Metastasis is a major cause of death from cancer in triple-negative breast cancer (TNBC). Apoptosis evasion is a critical feature of metastatic tumor cells. Chemopreventive and apoptotic potential of curcumin has been shown in breast cancer. However, the precise mechanism of these effects against metastatic tumor cells has not been clearly addressed yet. Methods: 4T1 cell line was used for induction of metastatic animal model of breast cancer. Primary and metastatic tumor cells were extracted from subcutaneous tumor and lung of cancerous mice, respectively. MTT assay was used to determine the effect of curcumin on viability of tumor cells. Quantitative real-time polymerase chain reaction was performed to analyze the effect of curcumin on death receptor-5 (DR-5) gene expression. Results: Our data revealed that, compared with primary tumor cells, metastatic tumor cells were more resistance to apoptosis effects of curcumin. The DR-5 gene expression was up-regulated in both primary and metastatic tumor cells after curcumin treatment, but this up-regulation was significantly higher in primary tumor cells compared with metastatic cells. Conclusion: These findings provided important insights regarding the molecular mechanism of apoptosis resistance of metastatic tumor cells and can be used for designing a targeted therapeutic strategies in combat with metastatic TNBC.

Curcumin: Modulator of Key Molecular Signaling Pathways in Hormone-Independent Breast Cancer

“…There is also a close relationship between dysregulated caspase expression and the development of hormone-independent breast cancer which is also involved in its clinicopathological features and poor overall survival [ 188 , 189 ]. Altered death receptor signaling also contributes to apoptosis resistance in breast cancer [ 190 , 191 , 192 ]. Collectively, given the critical role of apoptosis evasion in promoting the pathogenesis and progression of breast cancer tumors, therapeutic targeting of the apoptotic machinery in cancer cells holds great promise in the anticancer drug discovery and development.…”

Upregulation of MMPs in Metastatic Cascade of Breast Cancer To Brain

“…Primary and metastatic tumor cell extraction, was performed according to our and other group previous works [22][23][24][25]. Brie y primary tumor and brain of cancerous mice were excised after 35 days of tumor induction in mice, and surface blood was removed by rinsing it in PBS.…”

FePd Nanozyme- and SKN-Encapsulated Functional Lipid Nanoparticles for Cancer Nanotherapy via ROS-Boosting Necroptosis

“…Tumoral apoptosis or programmed cell death has been considered an essential homeostatic mechanism that maintains cell generation with cell death. However, apoptotic resistance, like defects in the apoptotic pathway, has become an urgent clinical problem, which greatly limits the therapeutic efficacy because conventional chemotherapy and irradiation work primarily by inducing apoptosis. − Based on this, much attention has been focused on the explorations against apoptotic resistance. , However, the resulting apoptotic defects in tumors are various and complex, including overexpression of antiapoptotic proteins, mutations of proapoptotic proteins, loss of caspase, or overexpression of drug transporters. − Therefore, it always remains a great challenge to reverse the resistance of apoptosis via a simple one-pathway intervention. Luckily, necroptosis, another form of regulated cell death, has become a probable and intrinsic pathway of tumors against apoptotic resistance. − …”