Triple-negative breast cancer (TNBC), which accounts for 15-20% of all breast cancers, does not express estrogen receptor (ER) or progesterone receptor (PR) and lacks human epidermal growth factor receptor 2 (HER2) overexpression or amplification. These tumors have a more aggressive phenotype and a poorer prognosis due to the high propensity for metastatic progression and absence of specific targeted treatments. Patients with TNBC do not benefit from hormonal or trastuzumab-based targeted therapies because of the loss of target receptors. Although these patients respond to chemotherapeutic agents such as taxanes and anthracyclines better than other subtypes of breast cancer, prognosis remains poor. A group of targeted therapies under investigation showed favorable results in TNBC, especially in cancers with BRCA mutation. The lipid-lowering statins (3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors), including lovastatin and simvastatin, have been shown to preferentially target TNBC compared with non-TNBC. These statins hold great promise for the management of TNBC. Only with the understanding of the molecular basis for the preference of statins for TNBC and more investigations in clinical trials can they be reformulated into a clinically approved drug against TNBC.

Doxorubicin (DOX), also known as adriamycin, is a DNA topoisomerase II inhibitor and belongs to the family of anthracycline anticancer drugs. DOX is used for the treatment of a wide variety of cancer types. However, resistance among cancer cells has emerged as a major barrier to effective treatment using DOX. Currently, the role of autophagy in cancer resistance to DOX and the mechanisms involved have become one of the areas of intense investigation. More and more preclinical data are being obtained on reversing DOX resistance through modulation of autophagy as one of the promising therapeutic strategies. This review summarizes the recent advances in autophagy-targeting therapies that overcome DOX resistance from in-vitro studies to animal models for exploration of novel delivery systems. In-depth understanding of the mechanisms of autophagy regulation in relation to DOX resistance and development of molecularly targeted autophagy-modulating agents will provide a promising therapeutic strategy for overcoming DOX resistance in cancer treatment.

Cancer stem cells reside in a distinct microenvironment called niche. The reciprocal interactions between cancer stem cells and niche contribute to the maintenance and enrichment of cancer stem cells. In order to simulate the interactions between cancer stem cells and niche, three-dimensional models have been developed. These in vitro culture systems recapitulate the spatial dimension, cellular heterogeneity, and the molecular networks of the tumor microenvironment and show great promise in elucidating the pathophysiology of cancer stem cells and designing more clinically relavant treatment modalites.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with a higher risk in younger women and a poorer prognosis and without targeted therapies available currently. Cancer stem cells (CSCs) are increasingly recognized as the main cause of treatment failure and tumor recurrence. The present paper reports the encapsulation of lovastatin (LV) into cerasomes. Compared with free LV, cerasome-encapsulated LV (C-LV) nanohybrids showed cytotoxicity to MDA-MB-231 CSCs in a dose- and time-dependent manner. Furthermore, intravenous injection of C-LV nanohybrids resulted in a significant tumor size reduction in a dose-dependent manner in xenograft tumors derived from subcutaneous inoculation of MDA-MB-231 cells. Furthermore, histopathological and/or immunohistochemical analysis revealed that C-LV nanohybrids significantly induced mammary gland formation and apoptosis and inhibited angiogenesis, the CSC phenotype, and the epithelial-to-mesenchymal transition in xenograft tumors. Most importantly, C-LV nanohybrids were found to be more effective than free LV in inhibiting the growth of breast cancer xenografts and the stemness properties in vivo. To the best of our knowledge, ours is the first demonstration of nanohybrids for efficient inhibition of CSCs derived from TNBC, offering a new option for the TNBC treatment.

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer worldwide. Despite the decrease in mortality of CRC patients, further investigation of the molecular pathogenesis of CRC could unveil new therapeutic targets and offer better prognosis predictions, which might direct attention to epigenetic regulators. Methods: Publicly available data from the Gene Expression Omnibus (GEO) database and clinical samples were collected. Bioinformatics methods were used to screen hub genes expressed in CRC. qRT-PCR and Western blotting were used to experimentally determine the expression of one gene of interest, the helicase lymphoid-specific (HELLS) gene, at the RNA and protein levels. Immunohistochemical (IHC) assays were used to correlate the stained HELLS proteins to survival data. Cell proliferation levels were assayed by a CCK-8 kit, a colony formation assay was performed, and flow cytometry was used to quantify the cells at each stage of the cell cycle. Results: A total of 225 overlapping genes were screened, including 14 hub genes. Analysis through a protein-protein interaction (PPI) network and the Gene Ontology database was performed by using the Cytoscape and DAVID online tools, respectively. HELLS RNA and protein expression levels in tumor tissues were 2.09-fold higher and 1.46-fold higher, respectively, than in the peritumoral tissues (p < 0.001, p<0.001). HELLS expression was significantly associated with the T stage (p=0.0027), M stage (p=0.0119), and TNM clinical stage (p = 0.0312) and a higher pathological grade (p=0.049). Highly expressed HELLS was reversibly associated with overall survival (log-rank p = 0.027). HELLS siRNA impaired cell proliferation and colony generation in vitro. HELLS siRNA induced significant G2+M arrest in HT29 and HCT116 cells compared with the respective negative controls (82.29% vs 25.85% and 35.41% vs 15.26%, respectively). Conclusion: Our data revealed that HELLS was significantly upregulated in CRC and correlated with clinicopathological parameters. High expression of HELLS indicated poor prognosis for CRC patients. HELLS knockdown led to impaired cell proliferation, colony generation, and G 2 +M cell cycle arrest.

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignancy occurring at high incidence in Southeast Asia and southern China. In spite of the good response to radio- and chemo-therapy at the early stage, resistance and recurrence develop in NPC patients in the advanced setting. Cancer stem cells (CSCs) play an important role in drug resistance and cancer recurrence. Here we report that lovastatin, a natural compound and a lipophilic statin that has already been used in the clinic to treat hypercholesterolemia, inhibited the CSC properties and induced apoptosis and cell cycle arrest in sphere-forming cells derived from the 5-8F and 6-10B NPC cell lines. Furthermore, lovastatin conferred enhanced sensitivity to the chemotherapeutic and photodynamic agents in NPC CSCs. Together our findings suggest that targeting CSCs by lovastatin in combination with routine chemotherapeutic drugs or photodynamic therapy might be a promising approach to the treatment of NPC.

Triple-negative breast cancer (TNBC) is more aggressive and has poorer prognosis compared to other subtypes of breast cancer. Epithelial-to-mesenchymal transition (EMT) is a process in which epithelial cells transform into mesenchymal-like cells capable of migration, invasion, and metastasis. Recently, we have demonstrated that lovastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor and a lipid-lowering drug, could inhibit stemness properties of cancer stem cells (CSCs) derived from TNBC cell in vitro and in vivo. This study is aimed at investigating whether lovastatin inhibits TNBC CSCs by inhibiting EMT and suppressing metastasis and the mechanism involved. In the present study, we found that lovastatin dysregulated lysine succinylation of cytoskeleton-associated proteins in CSCs derived from TNBC MDA-MB-231 cell. Lovastatin inhibited EMT as demonstrated by down-regulation of the protein levels of Vimentin and Twist in MDA-MB-231 CSCs in vitro and vivo and by reversal of TGF-β1-induced morphological change in MCF10A cells. Lovastatin also inhibited the migration of MDA-MB-231 CSCs. The disruption of cytoskeleton in TNBC CSCs by lovastatin was demonstrated by the reduction of the number of pseudopodia and the relocation of F-actin cytoskeleton. Combination of lovastatin with doxorubicin synergistically inhibited liver metastasis of MDA-MB-231 CSCs. Bioinformatics analysis revealed that higher expression levels of cytoskeleton-associated genes were characteristic of TNBC and predicted survival outcomes in breast cancer patients. These data suggested that lovastatin could inhibit the EMT and metastasis of TNBC CSCs in vitro and in vivo through dysregulation of cytoskeleton-associated proteins.

The nucleolus is a dynamic structure that has roles in various physiological and pathophysiological processes. Perturbations on many aspects of the nucleolar functions are thought to cause “nucleolar stress”, which occurs in response to a variety of chemotherapeutic drugs. The main characteristic changes of nucleolar stress include: 1) reduction of the size and volume of the nucleolus; 2) inhibition of RNA Pol I-mediated rRNA synthesis; and 3) nucleoplasmic translocation of nucleolar stress-related proteins. In studying the apoptosis-inducing effect of the natural compound lovastatin (LV) on breast cancer stem cells, we unexpectedly uncovered a novel form of nucleolar stress, which we call “reverse nucleolar stress”. In our system, the canonical nucleolus stress inducer doxorubicin caused nucleoplasmic translocation of the nucleolar protein NPM and complete abolishment of Nolc1, an NPM-interacting protein and an activator of rRNA transcription. In contrast, the reverse nucleolar stress induced by LV is manifested as a more localized perinucleolar distribution of NPM and an increase in the protein level of Nolc1. Furthermore, translocation of the ribosomal protein RPL3 from the cytoplasm to the nucleolus and increased AgNOR staining were observed. These changes characterize a novel pattern of nucleolar stress doubtlessly distinguishable from the canonical one. The functional consequences of reverse nucleolar stress are not clear at present but may presumably be related to cell death or even normalization of the stressed cell. The discovery of reverse nucleolar stress opens up a new area of research in molecular and cellular biology and might have important implications in cancer therapy.