Downregulation of reticulocalbin‐1 differentially facilitates apoptosis and necroptosis in human prostate cancer cells

• Published in: Cancer science Vol. 109; no. 4; pp. 1147 - 1157
• Main Authors: Liu, Xiaofei, Zhang, Nianzhao, Wang, Dawei, Zhu, Deyu, Yuan, Quan, Zhang, Xiulei, Qian, Lilin, Niu, Huanmin, Lu, Yi, Ren, Guijie, Tian, Keli, Yuan, Huiqing
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.04.2018; John Wiley and Sons Inc
• Subjects: AKT protein; Animals; Apoptosis; Apoptosis - genetics; Breast cancer; Ca2+/calmodulin-dependent protein kinase II; Calcium (reticular); Calcium-binding protein; Calcium-Binding Proteins - genetics; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics; Cancer therapies; Caspase; Caspases - genetics; Cell activation; Cell adhesion & migration; Cell cycle; Cell Cycle Checkpoints - genetics; Cell death; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; Cell survival; Cell Survival - genetics; Cell viability; Cyclin B; Cyclin D1; Down-Regulation - genetics; Drug resistance; eIF-2 Kinase - genetics; Endoplasmic reticulum; Endoplasmic Reticulum Stress - genetics; Enzymes; Flow cytometry; G2 Phase Cell Cycle Checkpoints - genetics; Heat-Shock Proteins - genetics; Homeostasis; Humans; Kinases; Male; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Necroptosis; Necrosis - genetics; Original; Phosphorylation; Phosphorylation - genetics; Physiology; Prostate cancer; Prostatic Neoplasms - genetics; Proteins; PTEN protein; reticulocalbin 1; Roles; Software; Tensin; United States > US; China; Germany; apoptosis; prostate cancer; reticulocalbin 1; endoplasmic reticulum; necroptosis
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.13541

Reticulocalbin 1 (RCN1), an endoplasmic reticulum (ER)‐resident Ca2+‐binding protein, is dysregulated in cancers, but its pathophysiological roles are largely unclear. Here, we demonstrate that RCN1 is overexpressed in clinical prostate cancer (PCa) samples, associated with cyclin B, not cyclin D1 expression, compared to that of benign tissues in a Chinese Han population. Downregulation of endogenous RCN1 significantly suppresses PCa cell viability and arrests the cell cycles of DU145 and LNCaP cells at the S and G2/M phases, respectively. RCN1 depletion causes ER stress, which is evidenced by induction of GRP78, activation of PERK and phosphorylation of eIF2α in PCa cells. Remarkably, RCN1 loss triggers DU145 cell apoptosis in a caspase‐dependent manner but mainly causes necroptosis in LNCaP cells. An animal‐based analysis confirms that RCN1 depletion suppresses cell proliferation and promotes cell death. Further investigations reveal that RCN1 depletion leads to elevation of phosphatase and tensin homolog (PTEN) and inactivation of AKT in DU145 cells. Silencing of PTEN partially restores apoptotic cells upon RCN1 loss. In LNCaP cells, predominant activation of CaMKII is important for necroptosis in response to RCN1 depletion. Thus, RCN1 may promote cell survival and serve as a useful target for cancer therapy. Reticulocalbin‐1 (RCN1) is overexpressed in clinical prostate cancer (PCa) samples from the Chinese Han population. Knockdown of RCN1 triggers mitotic arrest in PCa cells, suppress cell viability and inhibits tumor growth on xenograft mice. RCN1 depletion elicits Ca2+ release from the ER to the cytoplasm via IP3 receptor on the ER, leading to the activation of ER stress and CaMKII, which at least in part contributes to induction of apoptosis in DU145 cells and necroptosis in LNCaP cells, respectively. Upon RCN1 silencing, elevation of PTEN and inactivation of AKT play a role in DU145 cellular apoptosis, whereas predominant activation of CaMKII is important for necroptosis in LNCaP cells.