ABSTRACT
BACKGROUND/AIM: Breast cancer is the most prevalent form of cancer among women worldwide, with a high mortality rate. While the most common cause of breast cancer death is metastasis, there is currently no potential treatment for patients at the metastatic stage. The present study investigated the potential of using a combination of HSP90 and mTOR inhibitor in the treatment of breast cancer cell growth, migration, and invasion. MATERIALS AND METHODS: Gene Expression Profiling Interactive Analysis (GEPIA) was used to investigate the gene expression profiles. Western blot analysis and fluorescence staining were used for protein expression and localization, respectively. MTT, wound healing, and transwell invasion assays were used for cell proliferation, migration, and invasion, respectively. RESULTS: GEPIA demonstrated that HSP90 expression was significantly higher in breast invasive carcinoma compared to other tumor types, and this expression correlated with mTOR levels. Treatment with 17-AAG, an HSP90 inhibitor, and Torkinib, an mTORC1/2 inhibitor, significantly inhibited cell proliferation. Moreover, combination treatment led to down-regulation of AKT. Morphological changes revealed a reduction in F-actin intensity, a marked reduction of YAP, with interference in nuclear localization. CONCLUSION: Targeting HSP90 and mTOR has the potential to suppress breast cancer cell growth and progression by disrupting AKT signaling and inhibiting F-actin polymerization. This combination treatment may hold promise as a therapeutic strategy for breast cancer treatment that ameliorates adverse effects of a single treatment.
Subject(s)
Actins , Breast Neoplasms , Cell Movement , Cell Proliferation , HSP90 Heat-Shock Proteins , Proto-Oncogene Proteins c-akt , TOR Serine-Threonine Kinases , Humans , HSP90 Heat-Shock Proteins/metabolism , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Female , TOR Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Cell Proliferation/drug effects , Cell Movement/drug effects , Phosphorylation/drug effects , Actins/metabolism , Actins/genetics , Cell Line, Tumor , Neoplasm Invasiveness , Signal Transduction/drug effects , Lactams, Macrocyclic/pharmacology , Benzoquinones/pharmacology , MTOR Inhibitors/pharmacology , Gene Expression Regulation, Neoplastic/drug effectsABSTRACT
Colorectal cancer (CRC) is a major worldwide health problem owing to its high prevalence and mortality rates. Carcinogenesis in the colon is a multistage and multifactorial process. An imbalance between free radical exposure and anti-oxidant defense systems may leads to oxidative stress and attack of macromolecules which can alter signal transduction pathways and gene expression. Consequently, oxidative damage can lead to cellular dysfunction and contribute to pathophysiological processes in a variety of diseases including CRC. One factor tightly associated with CRC is chronic inflammation, which can be present from the earliest stage of tumor onset. Unpolished rice is an attractive chemoprevention in CRC due to their anti-oxidant and anti-inflammatory activities. The aim of this paper is to review evidence linking oxidative stress and inflammation to CRC and to provide essential background information for understanding future research on oxidative stress and inflammation on CRC. Mechanisms of action of unpolished rice in CRC carcinogenesis are also discussed.
