Combination therapy induces unfolded protein response and cytoskeletal rearrangement leading to mitochondrial apoptosis in prostate cancer

Kumar, Sandeep; Chaudhary, Ajay Kumar; Kumar, Rahul; O’Malley, Jordan; Dubrovska, Anna; Wang, Xinjiang; Yadav, Neelu; Goodrich, David W.; Chandra, Dhyan

doi:10.1016/j.molonc.2016.03.007

Cited by 9 publications

(5 citation statements)

References 79 publications

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“…The caspase-3 activity in cell lysates of Capan-1 cells were determined as earlier described method [ 43 ]. Briefly, whole-cell extract were prepared from control and GNE-495 treated (24 h) Capan-1 cells using NP-40 lysis buffer.…”

Section: Methodsmentioning

confidence: 99%

MAP4K4 promotes pancreatic tumorigenesis via phosphorylation and activation of mixed lineage kinase 3

et al. 2021

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MAP4K4 is a Ste20 member and reported to play important roles in various pathologies, including in cancer. However, the mechanism by which MAP4K4 promotes pancreatic cancer is not fully understood. It is suggested that MAP4K4 might function as a cancer promoter via specific downstream target(s) in an organ-specific manner. Here we identified MLK3 as a direct downstream target of MAP4K4. The MAP4K4 and MLK3 associates with each other, and MAP4K4 phosphorylates MLK3 on Thr738 and increases MLK3 kinase activity and downstream signaling. The phosphorylation of MLK3 by MAP4K4 promotes pancreatic cancer cell proliferation, migration, and colony formation. Moreover, MAP4K4 is overexpressed in human pancreatic tumors and directly correlates with the disease progression. The MAP4K4-specific pharmacological inhibitor, GNE-495, impedes pancreatic cancer cell growth, migration, induces cell death, and arrests cell cycle progression. Additionally, the GNE-495 reduced the tumor burden and extended survival of the KPC mice with pancreatic cancer. The MAP4K4 inhibitor also reduced MAP4K4 protein expression, tumor stroma, and induced cell death in murine pancreatic tumors. These findings collectively suggest that MLK3 phosphorylation by MAP4K4 promotes pancreatic cancer, and therefore therapies targeting MAP4K4 might alleviate the pancreatic cancer tumor burden in patients.

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Section: Methodsmentioning

confidence: 99%

MAP4K4 promotes pancreatic tumorigenesis via phosphorylation and activation of mixed lineage kinase 3

et al. 2021

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“…Elucidating the mechanisms of signaling by the ER stress pathways in order to promote cell death or cell survival induction comprises a major focus in the field and will provide an important aspect of rational drug design for therapeutic applications against diverse diseases, including cancer. Indeed, our recent findings demonstrate that activation of UPR including mitochondrial UPR plays critical role during anticancer induced apoptosis in cancer cells [123, 124], suggesting that targeting UPR may provide novel strategies for cancer therapeutics. In this regard, one possibility is the development of small molecule modulators of the kinase components of the UPR ER , such as PERK and IRE1.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Endoplasmic reticulum-mediated unfolded protein response and mitochondrial apoptosis in cancer

Bhat

Chaudhary

Kumar

et al. 2017

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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104

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Abrogation of endoplasmic reticulum (ER) protein folding triggered by exogenous or endogenous factors, stimulates a cellular stress response, termed ER stress. ER stress reestablishes ER homeostasis through integrated signaling termed the ER-unfolded protein response (UPRER). In the presence of severe toxic or prolonged ER stress, the pro-survival function of UPRER is transformed into a lethal signal transmitted to and executed through mitochondria. Mitochondria are key for both apoptotic and autophagic cell death. Thus ER is vital in sensing and coordinating stress pathways to maintain overall physiological homeostasis. However, this function is deregulated in cancer, resulting in resistance to apoptosis induction in response to various stressors including therapeutic agents. Here we review the connections between ER stress and mitochondrial apoptosis, describing potential cancer therapeutic targets.

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“…The expression of cell surface marker CD44 was analyzed by immunofluorescence microscopy and flow cytometry as described earlier [43]. The expression of CD44 was analyzed by immunofluorescence using FITC tagged CD44 antibody and was used to detect CD44 expressions followed by counterstaining with DAPI.…”

Section: Methodsmentioning

confidence: 99%

Nimbolide reduces CD44 positive cell population and induces mitochondrial apoptosis in pancreatic cancer cells

et al. 2018

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Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive disease and current treatment regimens fail to effectively cure PDAC. Development of resistance to current therapy is one of the key reasons for this outcome. Nimbolide (NL), a triterpenoid obtained from Azadirachta indica, exhibits anticancer properties in various cancer including PDAC cells. However, the underlying mechanism of this anticancer agent in PDAC cells remains undefined. We show that NL exerts a higher level of apoptotic cell death compared to the first-line agent gemcitabine for PDAC, as well as other anticancer agents including sorafenib and curcumin. The anticancer efficacy of NL was further evidenced by a reduction in the CD44 as well as cancer stem-like cell (CSC) population, as it causes decreased sphere formation. Mechanistically, the anticancer efficacy of NL associates with reduced mutant p53 as well as increased mitochondrial activity in the form of increased mitochondrial reactive oxygen species and mitochondrial mass. Together, this study highlights the therapeutic potential of NL in mutant p53 expressing pancreatic cancer.

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Combination therapy induces unfolded protein response and cytoskeletal rearrangement leading to mitochondrial apoptosis in prostate cancer

Cited by 9 publications

References 79 publications

MAP4K4 promotes pancreatic tumorigenesis via phosphorylation and activation of mixed lineage kinase 3

MAP4K4 promotes pancreatic tumorigenesis via phosphorylation and activation of mixed lineage kinase 3

Endoplasmic reticulum-mediated unfolded protein response and mitochondrial apoptosis in cancer

Nimbolide reduces CD44 positive cell population and induces mitochondrial apoptosis in pancreatic cancer cells

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