Pleiotropic Role of HSF1 in Neoplastic Transformation

Author(s):

Natalia Vydra, Agnieszka Toma and Wieslawa WidlakPages 144-155 (12)

Abstract:

HSF1 (Heat Shock transcription Factor 1) is the main transcription factor activated in response to proteotoxic stress. Once activated, it induces an expression of heat shock proteins (HSPs) which enables cells to survive in suboptimal conditions. HSF1 could be also activated by altered kinase signaling characteristic for cancer cells, which is a probable reason for its high activity found in a broad range of tumors. There is rapidly growing evidence that HSF1 supports tumor initiation and growth, as well as metastasis and angiogenesis. It also modulates the sensitivity of cancer cells to therapy. Functions of HSF1 in cancer are connected with HSPs’ activity, which generally protects cells from apoptosis, but also are independent of its classical targets. HSF1-dependent regulation of non-HSPs genes plays a role in cell cycle progression, glucose metabolism, autophagy and drug efflux. HSF1 affects the key cell-survival and regulatory pathways, including p53, RAS/MAPK, cAMP/PKA, mTOR and insulin signaling. Although the exact mechanism of HSF1 action is still somewhat obscure, HSF1 is becoming an attractive target in anticancer therapies, whose inhibition could enhance the effects of other treatments.

Keywords:

Cancer, drug resistance, genomic instability, HSF1 inhibitors, HSPs, metastasis, p53 signaling.

Affiliation:

Cancer Center and Institute of Oncology, Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-101 Gliwice, Poland.

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Platycodin D Induces Tumor Growth Arrest by Activating FOXO3a Expression in Prostate Cancer in vitro and in vivo

Author(s):

Rui Zhou, Zongliang Lu, Kai Liu, Jing Guo, Jie Liu, Yong Zhou, Jian Yang, Mantian Mi and Hongxia XuPages 860-871 (12)

Abstract:

Platycodin D (PD), a major saponin derived from Platycodin grandiflorum, exerted cytotoxicity against prostate cancer cell lines (PC3, DU145 and LNCaP cells) with IC50 values in the range of 11.17 to 26.13μmol/L, whereas RWPE-1cells (a non-malignant human prostate epithelial cell line) were not significantly affected. A further study in these cell lines showed that PD could potently affect cell proliferation (indicated by the bromodeoxyuridine assay), induce cell apoptosis (determined by Annexin V-FITC flow cytometry) and cause cell cycle arrest (indicated by PI staining). After being treated with PD for 48 hours, DU145 and LNCaP cells were arrested in the G0 /G1 phase, and PC3 cells were arrested in the G2/M phase. A Western blotting analysis indicated that PD increased the expression of the FOXO3a transcription factor, decreased the expression of p-FOXO3a and MDM2 and increased the expression of FOXO-responsive genes, p21 and p27. MDM2 silencing (transiently by siRNA-MDM2) increased the PD-induced FOXO3a protein expression, while MDM2 overexpression (in cells transiently transfected with a pcDNA3-MDM2 plasmid) decreased the PD-induced expression of the FOXO3a protein. Moreover, PD dose-dependently inhibited the growth of PC3 xenograft tumors in BALB/c nude mice. A Western blotting analysis of the excised xenograft tumors indicated that similar changes in protein expression also occurred in vivo. These results suggest that PD exhibits significant activity against prostate cancer in vitro and in vivo. The FOXO3a transcription factor appears to be involved in the activity of PD. Together, all of these findings provide a basis for the future development of this agent for human prostate cancer therapy.

Keywords:

Cell cycle, FOXO3a, MDM2, Platycodin D, prostate cancer.

Affiliation:

Department of Nutrition, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, China.

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Cancer Stem Cells in Solid and Liquid Tissues of Breast Cancer Patients: Characterization and Therapeutic Perspectives

Author(s):

Rena Chiotaki, Hara Polioudaki and Panayiotis A. TheodoropoulosPages 256-269 (14)

Abstract:

Breast cancer stem cells (BCSCs) represent a heterogeneous subpopulation of rare cells within breast cancer tumors, displaying an enhanced tumor initiating capability and underlying disease progression and therapy resistance. Unraveling their phenotypic, biological and functional profile is a major challenge in the context of diminishing patient mortality. In this review, following a brief description on how cancer stem cells (CSCs) and their microenvironment contribute to tumor preservation and heterogeneity, we summarize the current literature regarding the molecular signature of BCSCs either localized in the primary tumor or circulating in the blood of breast cancer patients. We present recent data on specific stem and epithelial-to-mesenchymal transition (EMT) markers designating the BCSC subpopulation and underline their pathogenic significance. The molecular characterization of BCSCs has promoted the design of novel therapeutic approaches targeting the BCSC subpopulation which are currently being experimentally and clinically evaluated. We highlight recent advances on the development of novel BCSC-targeting therapeutic strategies including the inhibition of cell signaling pathways, differentiation therapy, metabolic interference and nucleotide-, bio- and nano-technology based approaches. Eliminating the chemo- and radio-resistance properties of breast cancer tumor cells via BCSC-directed therapies, combined to conventional therapeutic approaches, will augment the effectiveness of breast cancer treatment and improve the clinical outcome of breast cancer patients.

Keywords:

Breast cancer, cancer stem cells, circulating tumor cells, epithelial-to-mesenchymal transition, targeting of cancer stem cells.

Affiliation:

University of Crete, School of Medicine, P.O. Box 2208, 71003 Heraklion, Greece.

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A Comprehensive Outline of Trastuzumab Resistance Biomarkers in HER2 Overexpressing Breast Cancer

Author(s):

Otília Menyhart, Libero Santarpia and Balazs GyorffyPages 665-683 (19)

Abstract:

The introduction of trastuzumab for anti-HER2 therapy dramatically changed the clinical outcome for HER2 (ERBB2, neu) positive breast cancer patients. Today, patients eligible for trastuzumab are selected using HER2 expression/amplification status of the primary tumor. However, acquired and inherent resistance to anti-HER2 therapy in these patients poses a significant challenge, and better patient stratification will be needed to improve clinical response.

Here, we provide a wide-ranging overview of potential biomarkers capable of stratifying patients regarding their response to trastuzumab. These include HER2 amplification, impaired access to the binding site (p95HER2, Δ16HER-2, MUC4), augmented signaling through other ERBB family receptors (HER1, HER3, HER4) and their ligands, activation of HER2 targets by alternate heterodimers (EphA2, IGF-1R, GDF15, MUC1*), signaling triggered by downstream members (PIK3CA, PTEN, SRC, mTOR), altered expression of cell cycle and apoptotic regulators (CDKs, p27kip1, Bcl-2), hormone receptor status, resistance to antibody-dependent cellular cytotoxicity (FcγR), and altered miRNA expression signatures.

Multigenic molecular profile analyses have revealed further genes not directly associated with classical oncogenic pathways. Although numerous biomarkers have shown promise in pre-clinical studies, many have delivered controversial results when evaluated in clinical trials. One of the keys for targeting ERBB2 will be to consider the entire ERBB family and downstream associated pathways responsible for the malignant transformation.

The heterogeneity of the disease is likely to represent a significant obstacle to accurately predicting the course of resistance. The future most probably involves the incorporation of multiple biomarkers into a unified predictor enabling selection of patients for superior targeted drug administration.

Keywords:

Breast cancer, dimerization, HER2, molecular subtype, negative predictive biomarkers, survival, trastuzumab, tumor heterogeneity.

Affiliation:

MTA TTK Lendület Cancer Biomarker Research Group, Magyar Tudosok Korutja 2, H-1117 Budapest, Hungary.

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Advances in Synergistic Combinations of Chinese Herbal Medicine for the Treatment of Cancer

Author(s):

Xue-Qing Hu, Yang Sun, Eric Lau, Ming Zhao and Shi-Bing SuPages 346-356 (11)

Abstract:

The complex pathology of cancer development requires correspondingly complex treatments. The traditional application of individual single-target drugs fails to sufficiently treat cancer with durable therapeutic effects and tolerable adverse events. Therefore, synergistic combinations of drugs represent a promising way to enhance efficacy, overcome toxicity and optimize safety. Chinese Herbal Medicines (CHMs) have long been used as such synergistic combinations. Therefore, we summarized the synergistic combinations of CHMs used in the treatment of cancer and their roles in chemotherapy in terms of enhancing efficacy, reducing side effects, immune modulation, as well as abrogating drug resistance. Our conclusions support the development of further science-based holistic modalities for cancer care.

Keywords:

Cancer treatment, Chinese medicine, drug resistance, effect, immunity, side effects, synergistic combination.

Affiliation:

Department of Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

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