Cancer stem cells (CSCs) are comprised of a rare sub-population of cells in tumors that have been proposed to be responsible for high recurrence rates and resistance to chemotherapy. Galectins are highly expressed in cancers that correlate with the aggressiveness of tumors. Galectins may also promote the resistance of cancer cells to chemotherapy. However, the role of galectins in CSCs remains unknown. In this study, sphere formation was used to enrich H1299 human lung CSCs that had self-renewal ability, advanced tumorigenic potential, and that highly expressed stem/progenitor cell markers such as Oct4, Sox2, Nanog, and CD133. A novel candidate molecule, galectin-3, for stemness was found in lung CSCs. The expression of galectin-3 robustly increased in lung cancer spheres over serial passages, but its suppression in the H1299 monolayer or spheres resulted in reduced expression of stemness-related genes, sphere-forming ability, tumorigenicity, chemoresistance, and tumor initiation in mice. Notably, the overexpression of galectin-3 in A549 lung cancer cells, which have low capability to grow as tumor spheres, promoted CSC formation. β-catenin activity was increased in H1299 spheres and counteracted by galectin-3 suppression. Thus, galectin-3 may act as a cofactor by interacting with β-catenin to augment the transcriptional activities of stemness-related genes. Furthermore, galectin-3 expression correlated with tumor progression and expressions of β-catenin and CSC marker CD133 in lung cancer tissues. Targeting galectin-3 signaling may provide a new strategy for lung cancer treatment by inhibiting stem-like properties.

Ca2+ is pivotal intracellular messenger that coordinates multiple cell functions such as fertilization, growth, differentiation, and viability. Intracellular Ca2+ signaling is regulated by both extracellular Ca2+ entry and Ca2+ release from intracellular stores. Apart from working as the cellular recycling center, the lysosome has been increasingly recognized as a significant intracellular Ca2+ store that provides Ca2+ to regulate many cellular processes. The lysosome also talks to other organelles by releasing and taking up Ca2+. In lysosomal Ca2+-dependent processes, autophagy is particularly important, because it has been implicated in many human diseases including cancer. This review will discuss the major components of lysosomal Ca2+ stores and their roles in autophagy and human cancer progression.

Within the tumour microenvironment, a complex network of chemokines and their receptors affects the initiation and progression of tumours. The higher levels of tumour necrosis factor‐alpha (TNF‐α) are associated with tumour progression and an anti‐TNF‐α monoclonal antibody has been used successfully to treat patients with renal cell carcinoma (RCC). However, the role of chemokines and their receptors in the TNF‐α‐promoted progression of RCC remains unclear. In this study, TNF‐α was found to enhance the migration, invasion and epithelial‐mesenchymal transition (EMT) of RCC cells. To further investigate the molecular mechanism of TNF‐α on the progression of RCC, reverse transcription and quantitative PCR was used to screen chemokines and chemokine receptors that were associated with tumorigenesis. The results showed that TNF‐α significantly increased the expressions of CXCR2 and CXCR3 and their related ligands in RCC cells. Subsequently, we used a lentiviral shRNA system to knockdown the expression of CXCR2 and/or CXCR3 in RCC cells. CXCR2 and CXCR3 silencing inhibited the induction of Slug and ZEB‐1 with TNF‐α treatment of RCC cells. In addition, the knockdown of both CXCR2 and CXCR3 resulted in a greater decrease in cell migration, invasion and clonogenic ability compared with either CXCR2 or CXCR3 knockdown alone. Moreover, CXCR2 and CXCR3 silencing significantly reduced the sphere‐forming ability of RCC cells. High expression levels of CXCR2 and CXCR3 in cancer tissues correlated with tumour progression of renal cell carcinoma. These findings suggest that TNF‐α augments CXCR2 and CXCR3 to promote the progression of renal cell carcinoma leading to a poor prognosis.

These days, cancer can still not be effectively cured because cancer cells readily develop resistance to anticancer drugs. Therefore, an effective combination of drugs with different mechanisms to prevent drug resistance has become a very important issue. Furthermore, the BH3-only protein BNIP3 is involved in both apoptotic and autophagic cell death. In this study, lung cancer cells were treated with a chemotherapy drug alone or in combination to identify the role of BNIP3 and autophagy in combination chemotherapy for treating cancer. Our data revealed that various combinational treatments of two drugs could increase cancer cell death and cisplatin in combination with rapamycin or LBH589, which triggered the cell cycle arrest at the S phase. Cells with autophagosome and pEGFP-LC3 puncta increased when treated with drugs. To confirm the role of autophagy, cancer cells were pre-treated with the autophagy inhibitor 3-methyladenine (3-MA). 3-MA sensitized cancer cells to chemotherapy drug treatments. These results suggest that autophagy may be responsible for cell survival in combination chemotherapy for lung cancer. Moreover, BNIP3 was induced and localized in mitochondria when cells were treated with drugs. The transfection of a dominant negative transmembrane deletion construct of BNIP3 (BNIP3ΔTM) and treatment of a reactive oxygen species (ROS) inhibitor suppressed chemo drug-induced cell death. These results indicate that BNIP3 and ROS may be involved in combination chemo drug-induced cell death. However, chemo drug-induced autophagy may protect cancer cells from drug cytotoxicity. As a result, inhibiting autophagy may improve the effects of combination chemotherapy when treating lung cancer. K E Y W O R D S autophagy, BNIP3, combination chemotherapy, reactive oxygen species How to cite this article: Chung L-Y, Tang S-J, Wu Y-C, et al. Platinum-based combination chemotherapy triggers cancer cell death through induction of Bnip3 and ROS, but not autophagy.

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