New Ca2+ based anticancer nanomaterials trigger multiple cell death targeting Ca2+ homeostasis for cancer therapy.

Calcium ion (Ca2+) is a necessary element for human and Ca2+ homeostasis plays important roles in various cellular process and functions. Recent reaches have targeted on inducing Ca2+ overload (both intracellular and transcellular) for tumor therapy. With the development of nanotechnology, nanoplatform-mediated Ca2+ overload has been safe theranostic model for cancer therapy, and defined a special calcium overload-induced tumor cell death as "calcicoptosis". However, the underlying mechanism of calcicoptosis in cancer cells remains further identification. In this review, we summarized multiple cell death types due to Ca2+ overload that induced by novel anticancer nanomaterials in tumor cells, including apoptosis, autophagy, pyroptosis, and ferroptosis. We reviewed the roles of these anticancer nanomaterials on Ca2+ homeostasis, including transcellular Ca2+ influx and efflux, and intracellular Ca2+ change in the cytosolic and organelles, and connection of Ca2+ overload with other metal ions. This review provides the knowledge of these nano-anticancer materials-triggered calcicoptosis accompanied with multiple cell death by regulating Ca2+ homeostasis, which could not only enhance their efficiency and specificity, but also enlighten to design new cancer therapeutic strategies and biomedical applications.

Inhibiting stanniocalcin 2 reduces sunitinib resistance of Caki-1 renal cancer cells under hypoxia condition.

Background: Our previous study has suggested that blocking stanniocalcin 2 (STC2) could reduce sunitinib resistance in clear cell renal cell carcinoma (ccRCC) under normoxia. The hypoxia is a particularly important environment for RCC occurrence and development, as well as sunitinib resistance. The authors proposed that STC2 also plays important roles in RCC sunitinib resistance under hypoxia conditions. Methods: The ccRCC Caki-1 cells were treated within the hypoxia conditions. Real-time quantitative PCR and Western blotting were applied to detect the STC2 expression in ccRCC Caki-1 cells. STC2-neutralizing antibodies, STC2 siRNA, and the recombinant human STC2 (rhSTC2) were used to identify targeting regulation on STC2 in modulating sunitinib resistance, proliferation, epithelial-mesenchymal transition (EMT), migration, and invasion. In addition, autophagy flux and the lysosomal acidic environment were investigated by Western blotting and fluorescence staining, and the accumulation of sunitinib in cells was observed with the addition of STC2-neutralizing antibodies and autophagy modulators. Results: Under hypoxia conditions, sunitinib disrupted the lysosomal acidic environment and accumulated in Caki-1 cells. Hypoxia-induced the STC2 mRNA and protein levels in Caki-1 cells. STC2-neutralizing antibodies and STC2 siRNA effectively aggravated sunitinib-reduced cell viability and proliferation, which were reversed by rhSTC2. In addition, sunitinib promoted EMT, migration, and invasion, which were reduced by STC2-neutralizing antibodies. Conclusion: Inhibiting STC2 could reduce the sunitinib resistance of ccRCC cells under hypoxia conditions.

Calcium-Sensing Receptor (CaSR)-Mediated Intracellular Communication in Cardiovascular Diseases.

The calcium-sensing receptor (CaSR), a G-protein-coupled receptor (GPCR), is a cell-surface-located receptor that can induce highly diffusible messengers (IP3, Ca2+, cAMP) in the cytoplasm to activate various cellular responses. Recently, it has also been suggested that the CaSR mediates the intracellular communications between the endoplasmic reticulum (ER), mitochondria, nucleus, protease/proteasome, and autophagy-lysosome, which are involved in related cardiovascular diseases. The complex intracellular signaling of this receptor challenges it as a valuable therapeutic target. It is, therefore, necessary to understand the mechanisms behind the signaling characteristics of this receptor in intracellular communication. This review provides an overview of the recent research progress on the various regulatory mechanisms of the CaSR in related cardiovascular diseases and the heart-kidney interaction; the associated common causes are also discussed.

Blocking stanniocalcin 2 reduces sunitinib resistance in clear cell renal cell carcinoma.

Stanniocalcin 2 (STC2) has been identified as a prognostic marker in renal cell carcinoma. However, the role of STC2 in renal cell carcinoma is still unclear. In this study, we investigated the relationship between high expression of STC2 and sunitinib resistance in cells and the underlying mechanism. Through GEPIA platform analysis based on TCGA database, it showed that the expression of STC2 in kidney renal clear cell carcinoma (KIRC) was significantly higher than that in the normal population. Real-time quantitative PCR and western blotting detected significantly higher expression levels of STC2 in clear cell renal cell carcinoma (ccRCC) cells than that in normal renal cells. Enzyme-linked immunosorbent assay (ELISA) determined whether there is a high secretion of STC2 in ccRCC cells. The sunitinib resistance could be significantly reduced by STC2 neutralizing antibody but aggravated by the addition of recombinant human STC2 in ccRCC cells. Sunitinib suppressed STC2 expression and secretion, destroyed lysosomal acidic pH, and accumulated in the cells. However, STC2 neutralizing antibody can reduce the accumulation of sunitinib in cells to improve the inhibitory efficiency of sunitinib on cell proliferation. This study suggested STC2 could serve as a potential novel target for the treatment of ccRCC, anti-STC2 antibody might be an option of immunotherapy in the future.