Review
Biochemistry & Molecular Biology
Pooja Mittal, Sujata Singh, Rajesh Sinha, Anju Shrivastava, Archana Singh, Indrakant Kumar Singh
Summary: MCL-1 plays a crucial role in cancer cells and its overexpression is associated with drug resistance. Advancements in selective MCL-1 inhibitors offer new therapeutic strategies for cancer treatment.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2021)
Article
Cell Biology
Flore Sneyers, Martijn Kerkhofs, Femke Speelman-Rooms, Kirsten Welkenhuyzen, Rita La Rovere, Ahmed Shemy, Arnout Voet, Guy Eelen, Mieke Dewerchin, Stephen W. G. Tait, Bart Ghesquiere, Martin D. Bootman, Geert Bultynck
Summary: Intracellular Ca2+ signals play a crucial role in various cellular processes. Research has shown that BAPTAi can induce apoptosis in cancer cells by inhibiting mTORC1 activity and impairing glycolysis, independent of Ca2+ signaling. Additionally, direct inhibition of PFKFB3 emerges as a potential therapeutic target in MCL-1-dependent cancers.
CELL DEATH & DISEASE
(2023)
Article
Cell Biology
Xinfang Yu, Li Zhou, Wenbin Liu, Lijun Liu, Feng Gao, Wei Li, Haidan Liu
Summary: Skp2 is highly expressed in human colorectal cancer and plays a role in promoting tumorigenesis by stabilizing Mcl-1. Blocking Skp2 expression reduces tumorigenic properties of CRC cells, while Skp2 deficiency enhances sensitivity of CRC cells to irradiation treatments.
CELL DEATH & DISEASE
(2022)
Review
Chemistry, Medicinal
Jingjing Liu, Fangkui Yin, Ziqian Wang, Ting Song, Zhichao Zhang
Summary: Mcl-1 inhibitors have shown great potential in cancer therapy, but their on-target toxicity to the heart limits their therapeutic window. Combining Mcl-1 inhibitors with targeted therapies or chemotherapies can improve safety by reducing the dosage. Additionally, technologies such as antibody-drug conjugates and proteolysis targeting chimeras could be utilized to enhance the therapeutic window.
EXPERT OPINION ON THERAPEUTIC PATENTS
(2023)
Article
Oncology
Viacheslav V. Senichkin, Nikolay V. Pervushin, Alexey V. Zamaraev, Elena V. Sazonova, Anton P. Zuev, Alena Y. Streletskaia, Tatiana A. Prikazchikova, Timofei S. Zatsepin, Olga V. Kovaleva, Elena M. Tchevkina, Boris Zhivotovsky, Gelina S. Kopeina
Summary: Apoptosis is a programmed cell death process regulated by genes and proteins, including the Bcl-2 protein family. Resistance of cancer cells to apoptosis is often associated with overexpression of antiapoptotic proteins. This study found that Bak and Bcl-xL protein regulate the sensitivity and resistance of cancer cells to Mcl-1 inhibition. BH3 mimetics targeting Mcl-1 have shown promise in cancer treatment.
Article
Multidisciplinary Sciences
Mariana Belen Vera, Olivia Morris-Hanon, German Ignacio Nogueiras, Luisina Belen Ripari, Myrian Ines Esquivel, Carolina Perez-Castro, Leonardo Romorini, Gustavo Emilio Sevlever, Maria Elida Scassa, Guillermo Agustin Videla-Richardson
Summary: The recurrence of Glioblastoma is partly caused by resistant glioma stem cells. In this study, Bcl-xL and Mcl-1 were found to be crucial in regulating patient-derived glioma stem cell survival. Combining Bcl-xL inhibitors with chemotherapeutic agents can lead to increased cell death, and the sensitivity to Bcl-xL inhibition is correlated with Noxa expression levels.
SCIENTIFIC REPORTS
(2022)
Article
Oncology
Manuel Beltran-Visiedo, Nelia Jimenez-Alduan, Rosana Diez, Marta Cuenca, Andrea Benedi, Alfonso Serrano-Del Valle, Gemma Azaceta, Luis Palomera, Victor Peperzak, Alberto Anel, Javier Naval, Isabel Marzo
Summary: This study explores the mechanism of dinaciclib-induced death and the enhancement it can provide in combination with different BH3 mimetics in MM cell lines and plasma cells from MM patients. The results show synergistic effects of dinaciclib-based combinations, especially with B-cell lymphoma 2 or B-cell lymphoma extra-large inhibitors, in MM cell lines with partial dependence on myeloid cell leukemia sequence 1 (MCL-1). Simultaneous treatment with dinaciclib and BH3 mimetics ABT-199 or A-1155463 also showed a synergistic effect in plasma cells from MM patients, ex vivo. These findings suggest potential therapeutic options for MM patients with cytogenetic alterations and poor prognosis.
MOLECULAR ONCOLOGY
(2023)
Article
Cell Biology
Helene Tourriere, Karim Chebli, Latifa Zekri, Brice Courselaud, Jean Marie Blanchard, Edouard Bertrand, Jamal Tazi
Summary: This study reveals that G3BP is a key player in stress granule (SG) assembly, and Ras signaling regulates G3BP dephosphorylation to promote SG formation. SGs are formed in the cytoplasm in response to various toxic agents and are believed to play a critical role in regulating mRNA metabolism during stress. The findings suggest that G3BP determines the fate of mRNAs during cellular stress and Ras signaling is involved in this process through regulating G3BP dephosphorylation.
JOURNAL OF CELL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Zonglong Hu, Fan Wei, Yi Su, Yafang Wang, Yanyan Shen, Yanfen Fang, Jian Ding, Yi Chen
Summary: In this study, it was found that pan-HDAC inhibitors exacerbate breast cancer metastasis through upregulation of NEDD9 and activation of FAK phosphorylation. However, FAK inhibitors can reverse this metastasis induced by pan-HDAC inhibitors, which suggests a potential combination therapy for breast cancer.
SIGNAL TRANSDUCTION AND TARGETED THERAPY
(2023)
Article
Multidisciplinary Sciences
Lindsey R. Pack, Leighton H. Daigh, Mingyu Chung, Tobias Meyer
Summary: CDK4/6 inhibitors not only suppress CDK2 activity by displacing p21 from CDK4 complexes, but also catalytically inhibit CDK4/6 independently of p21, potentially by broadening the displacement to p27 and CDK6-containing complexes, with the aim of increasing efficacy and overcoming resistance mechanisms.
NATURE COMMUNICATIONS
(2021)
Article
Multidisciplinary Sciences
Bokyung Kim, Jae-Jin Lee, Ji Soo Shin, Ji-Wan Suh, Sunhee Jung, Geum-Sook Hwang, Hee-Yoon Lee, Kong-Joo Lee
Summary: The small molecule phenylbutenoid dimer NMac1 has a novel anti-proliferative effect in metastatic breast cancer cells under glucose starvation conditions, by activating AMPK, reducing ATP synthesis, and lowering mitochondrial membrane potential through inhibition of OXPHOS complex I. Its derivative NMac24 is identified as the most effective compound in anti-proliferation, suggesting their potential as anti-cancer agents with cytotoxic effects selectively in glucose restricted cells.
SCIENTIFIC REPORTS
(2021)
Article
Cell Biology
Bahareh Tabanifar, Anbalagan Moorthy, Heng Hang Tsai, Srinivasaraghavan Kannan, Chandra S. Verma, Kanaga Sabapathy
Summary: This study reveals a mechanism of cell death mediated by JNK, involving the degradation of the anti-apoptotic protein APE1. Upon exposure to genotoxic stress, JNK interacts with APE1, leading to its ubiquitination and degradation, which ultimately triggers cell death.
Article
Oncology
Marissa Rashkovan, Robert Albero, Francesca Gianni, Pablo Perez-Duran, Hannah Miller, Adam L. Mackey, Elisabeth M. Paietta, Martin S. Tallman, Jacob M. Rowe, Mark R. Litzow, Peter H. Wiernik, Selina Luger, Maria Luisa Sulis, Rajesh K. Soni, Adolfo A. Ferrando
Summary: The early T-cell acute lymphoblastic leukemia (ETP-ALL) is genetically, immunophenotypically, and transcriptionally distinct from more mature T-cell acute lymphoblastic leukemia tumors. ETP-ALL exhibits specific metabolic circuitries involving increased biosynthesis of phospholipids and sphingolipids, and are specifically sensitive to the inhibition of the mevalonate pathway. Inhibition of cholesterol synthesis suppresses oncogenic AKT1 signaling and MYC expression, inhibiting the growth and survival of ETP-ALL cells.
Article
Oncology
Katrine Melvold, Mariaserena Giliberto, Linda Karlsen, Pilar Ayuda-Duran, Robert Hanes, Toril Holien, Jorrit Enserink, Jennifer R. Brown, Geir E. Tjonnfjord, Kjetil Tasken, Sigrid S. Skanland
Summary: Novel therapeutic strategy combining MEK inhibitors with Bcl-2 antagonist venetoclax shows potential for high-risk CLL patients, while MM cells also display sensitivity to this combination treatment. However, MCL cells are unresponsive to MEK inhibition. High expression of antiapoptotic proteins Mcl-1 and Bcl-xL predicts low sensitivity to trametinib + venetoclax, and co-treatment with inhibitors of these proteins can overcome low sensitivity. These findings highlight the therapeutic potential of MEK/Bcl-2 inhibition in leukemia and myeloma, with protein expression levels serving as predictive biomarkers for treatment sensitivities.
MOLECULAR ONCOLOGY
(2022)
Article
Immunology
Jianfeng Chen, Xinyi Zhang, Xianming Tan, Pengda Liu
Summary: Chen et al. develop an algorithm to identify enzyme-substrate-recognizing motif mutations in cancer. They find that BUD13 AGC kinase motif mutations inactivate the tumor suppressive E3 ligase Fbw7 and promote colon cancer growth. The researchers validate specific BUD13 mutations that enhance oncogenicity and interfere with Fbw7 complex formation. They also discover the significance of BUD13 in responding to mTOR inhibition for therapy selection.
JOURNAL OF EXPERIMENTAL MEDICINE
(2023)
Article
Oncology
Jingshan Tong, Xiao Tan, Xiangping Song, Man Gao, Denise Risnik, Suisui Hao, Kaylee Ermine, Peng Wang, Hua Li, Yi Huang, Jian Yu, Lin Zhang
Summary: This study found that CDK4/6 inhibitors promote immunogenic cell death of cancer cells by regulating the expression of p73 and DR5, enhancing the effects of chemotherapy and immune therapy.
Article
Oncology
Ying Han, Yinghui Peng, Shanshan Liu, Xinwen Wang, Changjing Cai, Cao Guo, Yihong Chen, Le Gao, Qiaoqiao Huang, Min He, Edward Shen, Jie Long, Jian Yu, Hong Shen, Shan Zeng
Summary: The expression of tRF3008A is reduced in colorectal cancer and is significantly correlated with advanced and metastatic disease. Patients with low tRF3008A expression have a shorter disease-free survival, and tRF3008A is regarded as an independent prognostic biomarker in colorectal cancer. Functionally, tRF3008A suppresses the proliferation and migration of colorectal cancer by inhibiting the expression of FOXK1.
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Alexis Espinal, Michael W. Epperly, Amitava Mukherjee, Renee Fisher, Donna Shields, Hong Wang, M. Saiful Huq, Diala Fatima Hamade, Anda M. Vlad, Lan Coffman, Ronald Buckanovich, Jian Yu, Brian J. Leibowitz, Jan-Peter van Pijkeren, Ravi B. Patel, Donna Stolz, Simon Watkins, Asim Ejaz, Joel S. Greenberger
Summary: Gavaging Lactobacillus reuteri-Interleukin-22 (LR-IL-22) improves the delivery of IL-22 to the irradiated intestine and effectively mitigates radiation damage. Compared to the control group, gavaging LR-IL-22 improves multiple biomarkers associated with radiation damage.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biology
Diala F. Hamade, Alexis Espinal, Jian Yu, Brian J. Leibowitz, Renee Fisher, Wen Hou, Donna Shields, Jan-Peter Van Pijkeren, Amitava Mukherjee, Michael W. Epperly, Anda M. Vlad, Lan Coffman, Hong Wang, M. Saiful Huq, Ravi Patel, Jason Huang, Joel S. Greenberger
Summary: Oral administration of the probiotic Lactobacillus reuteri that releases interleukin-22 (LR-IL-22) can mitigate damage to the intestine and facilitate therapeutic whole-abdomen irradiation (WAI) for ovarian cancer.
RADIATION RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Jingshan Tong, Xiao Tan, Suisui Hao, Kaylee Ermine, Xinyan Lu, Zhaojin Liu, Anupma Jha, Jian Yu, Lin Zhang
Summary: Targeting cyclin-dependent kinases (CDKs) has shown promising therapeutic potential against cancer. A recent study reveals that selective CDK4/6 inhibitors induce Death Receptor 5 (DR5) via p73, leading to increased sensitivity of colorectal cancer cells to therapy-induced apoptosis. This finding provides valuable insights into the anticancer mechanisms of CDKIs and their potential clinical applications in colorectal cancer.
Article
Biochemistry & Molecular Biology
Brian J. Leibowitz, Guangyi Zhao, Wenxin Xia, Yuhan Wang, Hang Ruan, Lin Zhang, Jian Yu
Summary: In this study, the researchers discovered that mTOR inhibition can effectively suppress the formation of intestinal polyps, reverse established polyps, and prolong the lifespan of APC(Min/+) mice. Everolimus reduces the levels of p-4EBP1, p-S6, and Myc in the polyps and induces apoptosis of cells with activated beta-catenin. This cell death is accompanied by ER stress, activation of the extrinsic apoptotic pathway, innate immune cell recruitment, and subsequent T-cell infiltration.
Article
Oncology
Diala F. Hamade, Michael W. Epperly, Renee Fisher, Wen Hou, Donna Shields, Jan-Peter van Pijkeren, Amitava Mukherjee, Jian Yu, Brian J. Leibowitz, Anda M. Vlad, Lan Coffman, Hong Wang, M. Saiful Huq, Ziyu Huang, Claude J. Rogers, Joel S. Greenberger
Summary: Irradiation can be an effective treatment for ovarian cancer, but its use is limited by intestinal toxicity. Strategies to mitigate toxicity are important and LR-IFN-beta, a genetically engineered probiotic, shows potential as a safe and feasible radiation mitigator. LR-IFN-beta protects the intestine, improves survival, and can potentially revolutionize OC patient management when combined with platinum/taxane-based chemotherapy.
Review
Pharmacology & Pharmacy
Haris Saeed, Brian J. Leibowitz, Lin Zhang, Jian Yu
Summary: MYC is a proto-oncogene that plays a crucial role in the development of cancer cells. It is frequently rearranged and amplified in hematologic malignancies and is associated with cancer progression and therapeutic resistance. Activation of specific signaling pathways increases Myc levels, leading to stress adaptation, metabolic reprogramming, and immune evasion. Targeting Myc has proven challenging, but recent advances in understanding its mechanisms have opened up potential strategies for treatment, especially in colorectal cancer.
DRUG RESISTANCE UPDATES
(2023)
Meeting Abstract
Oncology
Kaylee Ermine, Dongshi Chen, Peng Wang, Jian Yu, Lin Zhang
Meeting Abstract
Oncology
Bogdan Kochetov, Phoenix D. Bell, Rebecca Raphael, Benjamin J. Raymond, Brian J. Leibowitz, Jingshan Tong, Brenda Diergaarde, Jian Yu, Reetesh K. Pai, Robert E. Schoen, Lin Zhang, Aatur Singhi, Shikhar Uttam.
Meeting Abstract
Oncology
Kaylee A. Ermine, Dongshi Chen, Peng Wang, Jian Yu, Lin Zhang
Article
Biochemistry & Molecular Biology
Hang Ruan, Brian J. Leibowitz, Yingpeng Peng, Lin Shen, Lujia Chen, Charlie Kuang, Robert E. Schoen, Xinghua Lu, Lin Zhang, Jian Yu
Summary: Mutant KRAS plays a crucial role in colorectal cancer by promoting Myc translation and Myc-dependent stress adaptation and proliferation. The combination of two FDA-approved drugs, Bortezomib and Everolimus, has been found to be highly effective against mutant KRAS colorectal cancer cells. This combination rapidly depletes Myc protein and induces cell death through various pathways. The study also shows that mutant KRAS colorectal cancer cells with elevated basal Myc and p-eIF2 alpha are more sensitive to the BR combination and exhibit characteristics of stress adaptation and cell death.
MOLECULAR BIOMEDICINE
(2022)