scholarly journals Ion Channels: New Actors Playing in Chemotherapeutic Resistance

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 376 ◽  
Author(s):  
Philippe Kischel ◽  
Alban Girault ◽  
Lise Rodat-Despoix ◽  
Mohamed Chamlali ◽  
Silviya Radoslavova ◽  
...  
Keyword(s):  
Ion Channels ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Breast Cancers ◽  
Altered Expression ◽  
Acquired Drug Resistance ◽  
Therapeutic Modalities ◽  
Channel Expression ◽  
Systemic Agents ◽  
Resistance To Chemotherapy

In the battle against cancer cells, therapeutic modalities are drastically limited by intrinsic or acquired drug resistance. Resistance to therapy is not only common, but expected: if systemic agents used for cancer treatment are usually active at the beginning of therapy (i.e., 90% of primary breast cancers and 50% of metastases), about 30% of patients with early-stage breast cancer will have recurrent disease. Altered expression of ion channels is now considered as one of the hallmarks of cancer, and several ion channels have been linked to cancer cell resistance. While ion channels have been associated with cell death, apoptosis and even chemoresistance since the late 80s, the molecular mechanisms linking ion channel expression and/or function with chemotherapy have mostly emerged in the last ten years. In this review, we will highlight the relationships between ion channels and resistance to chemotherapy, with a special emphasis on the underlying molecular mechanisms.

GAMYB TF modulates bHLH142 and is homeostatically regulated by TDR TF during rice anther tapetal and pollen development

2021 ◽  
Author(s):  
Swee-Suak Ko ◽  
Min-Jeng Li ◽  
Yi-Cheng Ho ◽  
Chun-Ping Yu ◽  
Ting-Ting Yang ◽  
...  
Keyword(s):  
Pollen Development ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Specific Binding ◽  
Biological Functions ◽  
Altered Expression ◽  
Regulatory Pathways ◽  
E Box ◽  
And Function ◽  
Different Tissues

Abstract GAMYB, UDT1, TIP2/bHLH142, TDR, and EAT1/DTD are important transcription factors (TFs) that play a crucial role during rice pollen development. This study demonstrates that bHLH142 acts downstream of UDT1 and GAMYB and works as a “hub” in these two pollen pathways. We show that GAMYB modulates bHLH142 expression through specific binding to the MYB motif of bHLH142 promoter during early stage of pollen development; while TDR acts as a transcriptional repressor of the GAMYB modulation of bHLH142 by binding to the E-box close to the MYB motif on the promoter. The altered expression of TFs highlights the importance that a tight, precise, and coordinated regulation among these TFs is essential for normal pollen development. Most notably, this study illustrates the regulatory pathways of GAMYB and UDT1 that rely on bHLH142 in a direct and an indirect manner, respectively, and function in different tissues with distinct biological functions during pollen development. This study advances our understanding of the molecular mechanisms of rice pollen development.

scholarly journals Molecular Mechanisms of Trastuzumab Resistance in HER2 Overexpressing Breast Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Gabriel L. Fiszman ◽  
María A. Jasnis
Keyword(s):  
Breast Cancer ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Breast Cancers ◽  
Trastuzumab Resistance ◽  
Alternative Pathways ◽  
Downstream Signaling ◽  
Therapeutic Modalities

The epidermal growth factor receptor 2 (HER2) is a tyrosine kinase overexpressed in nearly 20% to 25% of invasive breast cancers. Trastuzumab is a humanized monoclonal antibody that targets HER2. The majority of patients with metastatic breast cancer initially respond to trastuzumab, however, within 1 year of treatment disease progresses. Several molecular mechanisms have been described as contributing to the development of trastuzumab resistance. They could be grouped as impaired access of trastuzumab to HER2, upregulation of HER2 downstream signaling pathways, signaling of alternative pathways, and impaired immune antitumor mechanisms. However, since many of them have overlapping effects, it would be of great clinical impact to identify the principal signaling pathways involved in drug resistance. Significant efforts are being applied to find other therapeutic modalities besides trastuzumab treatment to be used alone or in combination with current modalities.

Q-CROC-03: A prospective biopsy driven clinical trial to study the mechanisms of resistance to chemotherapy in triple-negative breast cancer patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS1139-TPS1139
Author(s):  
Adriana Aguilar-Mahecha ◽  
Josiane Lafleur ◽  
Carole Seguin ◽  
Catalin Liviu Dragos Mihalcioiu ◽  
Josee-Anne Roy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Limiting Factors ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Tumor Resistance ◽  
Cancer Subtypes ◽  
Resistance To Chemotherapy

TPS1139 Background: Resistance to chemotherapy or targeted agents is the cause of death in most patients dying of breast cancer and one of the major challenges presently faced by oncologists. In triple negative breast cancers (TNBCs), drug resistance emerges quicker than in other breast cancer subtypes and contributes to the poor prognosis seen in these patients. The lack of targeted therapies to treat TNBC highlights the important need to better understand the molecular mechanisms contributing to chemotherapy resistance in order to develop new therapeutic strategies. However, the difficulty in obtaining tissue samples from drug resistant tumors has been one of the limiting factors in this field of study. Methods: We have designed a prospective phase II clinical trial where paired biopsies are collected from chemotherapy resistant TNBCs (NCT01276899). Four needle core biopsies are collected before the initiation of treatment and 2 weeks before surgery or at the time of progression in the neoadjuvant and metastatic settings respectively. Metastatic sites eligible for biopsy include liver, lung, skin and lymph nodes. This study is presently recruiting at 5 major health centers in Quebec and will soon open in the USA. We have currently enrolled 13 patients in the neoadjuvant setting and 2 metastatic patients. Major challenges in patient enrolment will be discussed. We have standardized the methods of collection and processing of tissue and blood specimens to ensure their molecular integrity and compatibility with different genomic and proteomic molecular platforms. Analysis of tumor cellularity has been incorporated into our quality control and we have optimized the extraction of nucleic acids to obtain high yields and optimal quality. Paired biopsies will undergo Next Gen Sequencing, flow sorted aCGH analysis, gene expression and miRNA profiling as well as phosphoproteomic profiling using reverse phase protein arrays. Collection of clinical data will allow molecular profiling data to be linked to clinical response data so as to determine DNA, RNA and protein factors correlated with tumor resistance to chemotherapy.

scholarly journals Combined Proteomic and Physiological Analysis of Chloroplasts Reveals Drought and Recovery Response Mechanisms in Nicotiana benthamiana

Plants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1127
Author(s):  
Silin Chen ◽  
Ping Li ◽  
Shunling Tan ◽  
Xiaojun Pu ◽  
Ying Zhou ◽  
...  
Keyword(s):  
Drought Stress ◽  
Stress Responses ◽  
Nicotiana Benthamiana ◽  
Molecular Mechanisms ◽  
Carbon Fixation ◽  
Early Stage ◽  
Repair Process ◽  
Altered Expression ◽  
Subsequent Recovery ◽  
Recovery Response

Chloroplasts play essential roles in plant metabolic processes and stress responses by functioning as environmental sensors. Understanding chloroplast responses to drought stress and subsequent recovery will help the ability to improve stress tolerance in plants. Here, a combined proteomic and physiological approach was used to investigate the response mechanisms of Nicotiana benthamiana chloroplasts to drought stress and subsequent recovery. Early in the stress response, changes in stomatal movement were accompanied by immediate changes in protein synthesis to sustain the photosynthetic process. Thereafter, increasing drought stress seriously affected photosynthetic efficiency and led to altered expression of photosynthesis- and carbon-fixation-related proteins to protect the plants against photo-oxidative damage. Additional repair mechanisms were activated at the early stage of recovery to restore physiological functions and repair drought-induced damages, even while the negative effects of drought stress were still ongoing. Prolonging the re-watering period led to the gradual recovery of photosynthesis at both physiological and protein levels, indicating that a long repair process is required to restore plant function. Our findings provide a precise view of drought and recovery response mechanisms in N. benthamiana and serve as a reference for further investigation into the physiological and molecular mechanisms underlying plant drought tolerance.

scholarly journals Inhibition of CK1ε potentiates the therapeutic efficacy of CDK4/6 inhibitor in breast cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Fabin Dang ◽  
Li Nie ◽  
Jin Zhou ◽  
Kouhei Shimizu ◽  
Chen Chu ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Therapeutic Efficacy ◽  
Molecular Mechanisms ◽  
Protein Abundance ◽  
Breast Cancers ◽  
Acquired Drug Resistance ◽  
Clinical Potential ◽  
Marked Suppression

AbstractAlthough inhibitors targeting CDK4/6 kinases (CDK4/6i) have shown promising clinical prospect in treating ER+/HER2- breast cancers, acquired drug resistance is frequently observed and mechanistic knowledge is needed to harness their full clinical potential. Here, we report that inhibition of CDK4/6 promotes βTrCP1-mediated ubiquitination and proteasomal degradation of RB1, and facilitates SP1-mediated CDK6 transcriptional activation. Intriguingly, suppression of CK1ε not only efficiently prevents RB1 from degradation, but also prevents CDK4/6i-induced CDK6 upregulation by modulating SP1 protein stability, thereby enhancing CDK4/6i efficacy and overcoming resistance to CDK4/6i in vitro. Using xenograft and PDX models, we further demonstrate that combined inhibition of CK1ε and CDK4/6 results in marked suppression of tumor growth in vivo. Altogether, these results uncover the molecular mechanisms by which CDK4/6i treatment alters RB1 and CDK6 protein abundance, thereby driving the acquisition of CDK4/6i resistance. Importantly, we identify CK1ε as an effective target for potentiating the therapeutic efficacy of CDK4/6 inhibitors.

Breast carcinoma in young females below the age of 35 years - histopathological and prognostic significance

1970 ◽  
Vol 2 (3) ◽  
pp. 198-202
Author(s):  
D Ghartimagar ◽  
A Ghosh ◽  
OP Talwar ◽  
R Narasimhan
Keyword(s):  
Breast Carcinoma ◽  
Young Women ◽  
Early Stage ◽  
Prognostic Significance ◽  
Age Group ◽  
Breast Cancers ◽  
Young Females ◽  
Younger Age ◽  
Grade 3 ◽  
Group Grade

Background: Breast cancers rarely occur in young women but are known to have more aggressive behaviors and poorer outcome. We here compare the significance of breast carcinoma in female below the age of 35 to the age over 35 whose specimens were submitted to Manipal teaching hospital, Pokhara. Materials and Methods: All cases of mastectomy with carcinoma from January 2000 to September 2011 were included in the study. Clinical and histopathological datas of all cases were reviewed and collated. Results: A total of 148 mastectomy specimens were received, among which, 23 cases (16%) were below 35 years; whereas 125 cases (84%) were above 35 years of age. In both groups, Stage II was the commonest stage but stage III was much more common in older group (33% versus 9%) and stage I was more common in younger age group (39% versus 27%). Bloom Richardson grading showed that in the older age group, grade 1 is the commonest grade (50%) while in the younger group; grade 3 is the commonest (39%). Patients were followed for a varying period of 6 months to 5 years. Two cases (2% of followed up cases) in older group and 3 cases (15% of followed up cases) in the younger group showed recurrence. Conclusion: Breast carcinoma in the patients younger than 35 years though presented at an early stage has higher grade tumor and poorer outcome. DOI: http://dx.doi.org/10.3126/jpn.v2i3.6021 JPN 2012; 2(3): 198-202

Role of Resveratrol in Modulating microRNAs in Human Diseases: From Cancer to Inflammatory Disorder

2020 ◽  
Vol 28 (2) ◽  
pp. 360-376 ◽  
Author(s):  
Atefeh Amiri ◽  
Maryam Mahjoubin-Tehran ◽  
Zatollah Asemi ◽  
Alimohammad Shafiee ◽  
Sarah Hajighadimi ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Antioxidant Activities ◽  
Natural Compounds ◽  
Therapeutic Effects ◽  
Inflammatory Disorder ◽  
Inflammatory Disorders ◽  
Therapeutic Modalities ◽  
Anti Cancer ◽  
Current Therapies ◽  
Anti Inflammatory

: Cancer and inflammatory disorders are two important public health issues worldwide with significant socio.economic impacts. Despite several efforts, the current therapeutic platforms are associated with severe limitations. Therefore, developing new therapeutic strategies for the treatment of these diseases is a top priority. Besides current therapies, the utilization of natural compounds has emerged as a new horizon for the treatment of cancer and inflammatory disorders as well. Such natural compounds could be used either alone or in combination with the standard cancer therapeutic modalities such as chemotherapy, radiotherapy, and immunotherapy. Resveratrol is a polyphenolic compound that is found in grapes as well as other foods. It has been found that this medicinal agent displays a wide pharmacological spectrum, including anti-cancer, anti-inflammatory, anti-microbial, and antioxidant activities. Recently, clinical and pre-clinical studies have highlighted the anti-cancer and anti-inflammatory effects of resveratrol. Increasing evidence revealed that resveratrol exerts its therapeutic effects by targeting various cellular and molecular mechanisms. Among cellular and molecular targets that are modulated by resveratrol, microRNAs (miRNAs) have appeared as key targets. MiRNAs are short non-coding RNAs that act as epigenetic regulators. These molecules are involved in many processes that are involved in the initiation and progression of cancer and inflammatory disorders. Herein, we summarized various miRNAs that are directly/indirectly influenced by resveratrol in cancer and inflammatory disorders.

Genetic and Epigenetic Modulation of Drug Resistance in Cancer: Challenges and Opportunities

2020 ◽  
Vol 20 (14) ◽  
pp. 1114-1131 ◽  
Author(s):  
Kanisha Shah ◽  
Rakesh M. Rawal
Keyword(s):  
Drug Resistance ◽  
Drug Targets ◽  
Complex Disease ◽  
Cancer Therapies ◽  
Altered Expression ◽  
Acquired Drug Resistance ◽  
Challenges And Opportunities ◽  
Chemotherapeutic Treatment ◽  
Epigenetic Modulation ◽  
Targeted Drug Therapies

Cancer is a complex disease that has the ability to develop resistance to traditional therapies. The current chemotherapeutic treatment has become increasingly sophisticated, yet it is not 100% effective against disseminated tumours. Anticancer drugs resistance is an intricate process that ascends from modifications in the drug targets suggesting the need for better targeted therapies in the therapeutic arsenal. Advances in the modern techniques such as DNA microarray, proteomics along with the development of newer targeted drug therapies might provide better strategies to overcome drug resistance. This drug resistance in tumours can be attributed to an individual’s genetic differences, especially in tumoral somatic cells but acquired drug resistance is due to different mechanisms, such as cell death inhibition (apoptosis suppression) altered expression of drug transporters, alteration in drug metabolism epigenetic and drug targets, enhancing DNA repair and gene amplification. This review also focusses on the epigenetic modifications and microRNAs, which induce drug resistance and contributes to the formation of tumour progenitor cells that are not destroyed by conventional cancer therapies. Lastly, this review highlights different means to prevent the formation of drug resistant tumours and provides future directions for better treatment of these resistant tumours.

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