scholarly journals Therapeutic targeting of the PI4K2A/PKR lysosome network is critical for misfolded protein clearance and survival in cancer cells

Oncogene ◽  
2019 ◽  
Vol 39 (4) ◽  
pp. 801-813 ◽  
Author(s):  
Apar Pataer ◽  
Bulent Ozpolat ◽  
RuPing Shao ◽  
Neil R. Cashman ◽  
Steven S. Plotkin ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Prion Proteins ◽  
Misfolded Protein ◽  
Breast Cancer Patients ◽  
Protein Kinase R ◽  
Protein Clearance ◽  
Dependent Protein

Abstract The role of RNA-dependent protein kinase R (PKR) and its association with misfolded protein expression in cancer cells are unclear. Herein we report that PKR regulates misfolded protein clearance by preventing it release through exosomes and promoting lysosomal degradation of misfolded prion proteins in cancer cells. We demonstrated that PKR contributes to the lysosome function and regulates misfolded prion protein clearance. We hypothesized that PKR-associated lysosome function is critical for cancer but not normal cell survival, representing an effective approach for highly targeted cancer therapy. In screening a compound library, we identified two PKR-associated compounds 1 and 2 (Pac 1 and 2) did not affect normal cells but selectively induced cell death in cancer cells depending on their PKR expression status. Pac 1 significantly inhibited the growth of human lung and breast xenograft tumors in mice with no toxicity. Pac 1 binds to PI4K2A and disrupts the PKR/PI4K2A-associated lysosome complex, contributing to destabilization of cancer cell lysosomes and triggering cell death. We observed that PKR and PI4K2A play significant prognostic roles in breast cancer patients. These results demonstrate that targeting of a PI4K2A/PKR lysosome complex may be an effective approach for cancer therapy.

scholarly journals Target Misfolded Protein Clearance Pathway for Cancer Therapy

Proceedings ◽  
2020 ◽  
Vol 40 (1) ◽  
pp. 45
Author(s):  
Apar Pataer
Keyword(s):  
Cell Death ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Prion Proteins ◽  
Misfolded Protein ◽  
Breast Cancer Patients ◽  
Protein Kinase R ◽  
Protein Clearance ◽  
Dependent Protein

The role of RNA-dependent protein kinase R (PKR) and its association with misfolded protein expression in cancer cells are unclear. Herein we report that PKR regulates misfolded protein clearance by preventing it release through exosomes and promoting lysosomal degradation of misfolded prion proteins in cancer cells. We demonstrated that PKR contributes to the lysosome function and regulates misfolded prion protein clearance. We hypothesized that PKR-associated lysosome function is critical for cancer but not normal cell survival, representing an effective approach for highly targeted cancer therapy. In screening a compound library, we identified two PKR-associated compound 1 did not affect normal cells but selectively induced cell death in cancer cells depending on their PKR expression status. Pac 1 significantly inhibited the growth of human lung and breast xenograft tumors in mice with no toxicity. Pac 1 binds to PI4K2A and disrupts the PKR/PI4K2A associated lysosome complex, contributing to destabilization of cancer cell lysosomes and triggering cell death. We observed that PKR and PI4K2A play significant prognostic roles in breast cancer patients. These results demonstrate that targeting of a PI4K2A/PKR lysosome complex may be an effective approach for cancer therapy.

Preparing Professionals in Cancer Therapy

2012 ◽  
pp. 200-208
Author(s):  
Shiv Shanker Pandey ◽  
Vivek Ambastha ◽  
Budhi Sagar Tiwari
Keyword(s):  
Cancer Research ◽  
Cell Death ◽  
Cancer Therapy ◽  
Programmed Cell Death ◽  
Cancer Cells ◽  
Western World ◽  
Medical Oncologists ◽  
Broad Interest ◽  
Major Target

Cancer is currently the second biggest cause of death in the Western world. Cancer cells escape the normal process of programmed cell death i.e., fail to die on schedule. The ability of cancer cells to avoid programmed cell death and continue to proliferate is one of the fundamental hallmarks of cancer and is a major target of cancer therapy development. Universities and research institutes are playing a major role in progress of cancer research. The aim of this study is to attract graduates of different disciplines towards cancer research and bring together researchers from different disciplines with an interest in the role of programmed cell death in cancer therapy and exploitation of programmed cell death research for therapeutic targeting of cancer. In spite of this, it is of broad interest to make a bridge or to start collaborations in between basic researchers and medical oncologists as well as for pharmaceutical companies i.e., aim of this study is to bridging the gap between knowledge and its action or application.

Relevance of mitochondrial dysfunction during Sorafenib-induced cell death in liver cancer cells. Role of oxidative and nitrogen reactive species

2021 ◽  
Vol 165 ◽  
pp. 54
Author(s):  
Patricia de la Cruz-Ojeda ◽  
M. Ángeles Rodríguez-Hernández ◽  
Elena Navarro-Villarán ◽  
Paloma Gallego ◽  
Pavla Staňková ◽  
...  
Keyword(s):  
Cell Death ◽  
Liver Cancer ◽  
Mitochondrial Dysfunction ◽  
Cancer Cells ◽  
Reactive Species ◽  
Liver Cancer Cells ◽  
Nitrogen Reactive Species

Magneto Mitochondrial Dysfunction Mediated Cancer Cell Death Using Intracellular Magnetic Nano-Transducers

2021 ◽  
Author(s):  
Wooram Park ◽  
Seok-Jo Kim ◽  
Paul Cheresh ◽  
Jeanho Yun ◽  
Byeongdu Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Therapy ◽  
Mitochondrial Dysfunction ◽  
Cancer Cells ◽  
Cancer Cell ◽  
High Sensitivity ◽  
Intrinsic Pathway ◽  
Cancer Cell Death

Mitochondria are crucial regulators of the intrinsic pathway of cancer cell death. The high sensitivity of cancer cells to mitochondrial dysfunction offers opportunities for emerging targets in cancer therapy. Herein,...

scholarly journals Assessment of TRPV4 Channel and Its Role in Colorectal Cancer Cells

2019 ◽  
Vol 12 (2) ◽  
pp. 629-638
Author(s):  
N. N. Bahari ◽  
S. Y. N. Jamaludin ◽  
A. H. Jahidin ◽  
M. N. Zahary ◽  
A. B. Mohd Hilmi
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Death ◽  
Cancer Cells ◽  
Human Colorectal Cancer ◽  
Expression Levels ◽  
Pharmacological Modulation ◽  
Colorectal Cancer Cells ◽  
Ht 29

The transient receptor potential vanilloid member 4 (TRPV4) is a non-selective calcium (Ca2+)-permeable channel which is widely expressed in different types of tissues including the lungs, liver, kidneys and salivary gland. TRPV4 has been shown to serve as a cellular sensor where it is involved in processes such as osmoregulation, cell volume regulation and thermoregulation. Emerging evidence suggests that TRPV4 also plays important roles in several aspects of cancer progression. Despite the reported roles of TRPV4 in several forms of cancers, the role of TRPV4 in human colorectal cancer remains largely unexplored. In the present study, we sought to establish the potential role of TRPV4 in colorectal cancer by assessing TRPV4 expression levels and investigating whether TRPV4 pharmacological modulation may alter cell proliferation, cell cycle and cell death in colorectal cancer cells. Quantitative real-time PCR analysis revealed that TRPV4 mRNA levels were significantly lower in HT-29 cells than normal colon CCD-18Co cells. However, TRPV4 mRNA was absent in HCT-116 cells. Pharmacological activation of TRPV4 with GSK1016790A significantly enhanced the proliferation of HT-29 cells while TRPV4 inhibition using RN 1734 decreased their proliferation. Increased proliferation in GSK1016790A-treated HT-29 cells was attenuated by co-treatment with RN 1734. Pharmacological modulation of TRPV4 had no effect on the cell cycle progression but promoted cell death in HT-29 cells. Taken together, these findings suggest differential TRPV4 expression levels in human colorectal cancer cells and that pharmacological modulation of TRPV4 produces distinct effects on the proliferation and induces cell death in HT-29 cells.

scholarly journals Novel insights on targeting ferroptosis in cancer therapy

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Sipeng Zuo ◽  
Jie Yu ◽  
Hui Pan ◽  
Linna Lu
Keyword(s):  
Cell Death ◽  
Heart Disease ◽  
Cancer Therapy ◽  
Alzheimer Disease ◽  
Cellular Structure ◽  
Redox Balance ◽  
Regulated Cell Death ◽  
Novel Theory ◽  
The Relationship

Abstract Ferroptosis belongs to a novel form of regulated cell death. It is characterized by iron dependence, destruction of intracellular redox balance and non-apoptosis. And cellular structure and molecules level changes also occur abnormally during ferroptosis. It has been proved that ferroptosis exist widespreadly in many diseases, such as heart disease, brain damage or alzheimer disease. At the same time, the role of ferroptosis in cancer cannot be underestimated. More and more indications have told that ferroptosis is becoming a powerful weapon against cancer. In addition, therapies rely on ferroptosis have been applied to the clinic. Therefore, it is necessary to understand this newly discovered form of cell death and its connection with cancer. This review summarizes the mechanism of ferroptosis, ferroptosis inducers based on different targets and inspection methods. At last, we analyzed the relationship between ferroptosis and malignancies, in order to provide a novel theory basis for cancer treatment.

scholarly journals Neferine induces autophagy-dependent cell death in apoptosis-resistant cancers via ryanodine receptor and Ca2+-dependent mechanism

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Betty Yuen Kwan Law ◽  
Francesco Michelangeli ◽  
Yuan Qing Qu ◽  
Su-Wei Xu ◽  
Yu Han ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Ryanodine Receptor ◽  
Calcium Release ◽  
Receptor Activation ◽  
Autophagic Cell Death ◽  
Dependent Manner ◽  
Computational Docking ◽  
Calcium Dependent

AbstractResistance of cancer cells to chemotherapy is a significant clinical concern and mechanisms regulating cell death in cancer therapy, including apoptosis, autophagy or necrosis, have been extensively investigated over the last decade. Accordingly, the identification of medicinal compounds against chemoresistant cancer cells via new mechanism of action is highly desired. Autophagy is important in inducing cell death or survival in cancer therapy. Recently, novel autophagy activators isolated from natural products were shown to induce autophagic cell death in apoptosis-resistant cancer cells in a calcium-dependent manner. Therefore, enhancement of autophagy may serve as additional therapeutic strategy against these resistant cancers. By computational docking analysis, biochemical assays, and advanced live-cell imaging, we identified that neferine, a natural alkaloid from Nelumbo nucifera, induces autophagy by activating the ryanodine receptor and calcium release. With well-known apoptotic agents, such as staurosporine, taxol, doxorubicin, cisplatin and etoposide, utilized as controls, neferine was shown to induce autophagic cell death in a panel of cancer cells, including apoptosis-defective and -resistant cancer cells or isogenic cancer cells, via calcium mobilization through the activation of ryanodine receptor and Ulk-1-PERK and AMPK-mTOR signaling cascades. Taken together, this study provides insights into the cytotoxic mechanism of neferine-induced autophagy through ryanodine receptor activation in resistant cancers.

Sign in / Sign up

Export Citation Format

Share Document