Rac1 signaling protects monocytic AML cells expressing the MLL-AF9 oncogene from caspase-mediated apoptotic death

Hinterleitner, Clemens; Huelsenbeck, Johannes; Henninger, Christian; Wartlick, Friedrich; Schorr, Anne; Kaina, Bernd; Fritz, Gerhard

doi:10.1007/s10495-013-0842-6

Cited by 13 publications

(8 citation statements)

References 61 publications

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“…Both values are roughly consistent with published IC 50 values for these drugs in different systems [e.g. 12.5 µM for EHT-1864-induced cancer cell apoptosis (Hinterleitner et al, 2013) and 2.5 µM for inhibition of Pak1 kinase activity by IPA-3 (Deacon et al, 2008)]. …”

Section: (B) Flim Images Of Hek293t Cells Expressing Il-4rα-cypet In supporting

confidence: 90%

Essential role of endocytosis for Interleukin-4 receptor mediated JAK/STAT signalling

Kurgonaite

Gandhi

Kurth

et al. 2015

Journal of Cell Science

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Many important signalling cascades operate through specialized signalling endosomes, but a corresponding mechanism has as yet not been described for hematopoietic cytokine receptors. Based on live-cell affinity measurements, we recently proposed that ligandinduced interleukin-4 receptor (IL-4R) complex formation and thus JAK/STAT pathway activation requires a local subcellular increase in receptor density. Here, we show that this concentration step is provided by the internalization of IL-4R subunits through a constitutive, Rac1-, Pak-and actin-mediated endocytosis route that causes IL-4R subunits to become enriched by about two orders of magnitude within a population of cortical endosomes. Consistently, ligand-induced receptor dimers are preferentially detected within these endosomes. IL-4 signalling can be blocked by pharmacological inhibitors targeting the actin polymerization machinery driving receptor internalization, placing endocytosis unambigously upstream of receptor activation. Taken together, these observations demonstrate a role for endocytosis that is mechanistically distinct from the scaffolding function of signalling endosomes in other pathways.

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Section: (B) Flim Images Of Hek293t Cells Expressing Il-4rα-cypet In supporting

confidence: 90%

Essential role of endocytosis for Interleukin-4 receptor mediated JAK/STAT signalling

Kurgonaite

Gandhi

Kurth

et al. 2015

Journal of Cell Science

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“…Remarkably, ZINC69391 showed low micromolar IC50 values in all cell lines tested, independently on their hematopoietic cell differentiation stage or lineage. In fact, previous reports showed that leukemic cells with MLL (Mixed Lineage Leukemia) rearrangements were specifically vulnerable to Rac1 inhibition, while cell lines such as HL-60, U937 and Jurkat were more resistant [ 10 , 40 ]. Our data show that ZINC69391 treatment inhibited cell proliferation of leukemic cells despite the fact that all cell lines tested here do not harbor MLL rearrangements.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Rac1 inhibitors with selective apoptotic activity in human acute leukemic cell lines

et al. 2017

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Rac1 GTPase has long been recognized as a critical regulatory protein in different cellular and molecular processes involved in cancer progression, including acute myeloid leukemia. Here we show the antitumoral activity of ZINC69391 and 1A-116, two chemically-related Rac1 pharmacological inhibitors, on a panel of four leukemic cell lines representing different levels of maturation. Importantly, we show that the main mechanism involved in the antitumoral effect triggered by the Rac1 inhibitors comprises the induction of the mitochondrial or intrinsic apoptotic pathway. Interestingly, Rac1 inhibition selectively induced apoptosis on patient-derived leukemia cells but not on normal mononuclear cells. These results show the potential therapeutic benefits of targeting Rac1 pathway in hematopoietic malignancies.

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“…Additionally, in human liver injured by doxorubicin and other genotoxic stresses, Rac1 activity was demonstrated to be necessary to protect oncogene-transformed acute myeloid leukemia (AML) cells against apoptosis in the presence of DNA double-strand breaks (DSBs) induced by lipidlowering drugs that inhibit cholesterol synthesis [45]. This association is because in AML cells, the ATR pathway is disturbed when the MLL-AF9 oncogene is overexpressed [46].…”

Section: Discussionmentioning

confidence: 99%

Rac1 GTPase-deficient HeLa cells present reduced DNA repair, proliferation, and survival under UV or gamma irradiation

et al. 2015

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Rac1 GTPase controls essential cellular functions related to the cytoskeleton, such as motility and adhesion. Rac1 is overexpressed in many tumor cells, including breast cancers, where it is also involved in the proliferation and checkpoint control necessary for the cell's recovery after exposure to ionizing radiation. However, its role in DNA damage and repair remains obscure in other tumor cells and under different genotoxic conditions. Here, we compare HeLa cells with mutants exogenously expressing a dominant-negative Rac1 (HeLa-Rac1-N17) by their responses to DNA damage induced by gamma or UV radiation. In HeLa cells, these treatments led to increased levels of active Rac1 (Rac1-GTP) and of stress fibers, with a diminished ability to migrate compared to untreated cells. However, the reduction of Rac1-GTP in Rac1-N17-deficient clones resulted in much higher levels of polymerized stress fibers accompanied by a strong impairment of cell migration, even after both radiation treatments. With regard to proliferation and genomic stability, dominant-negative Rac1 cells were more sensitive to gamma and UV radiation, exhibiting reduced proliferation and survival consistent with increased DNA damage and delayed or reduced DNA repair observed in this Rac1-deficient clone. The DNA damage response, as indicated by pH2AX and pChk1 levels, was increased in HeLa cells but was not effectively triggered in the Rac1-N17 clone after radiation treatment, which is likely the main cause of DNA damage accumulation. These data suggest that Rac1 GTPase plays an important role in signaling and contributes to the sensitivity of cervical cancer cells under UV or gamma radiation treatments.

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Rac1 signaling protects monocytic AML cells expressing the MLL-AF9 oncogene from caspase-mediated apoptotic death

Cited by 13 publications

References 61 publications

Essential role of endocytosis for Interleukin-4 receptor mediated JAK/STAT signalling

Essential role of endocytosis for Interleukin-4 receptor mediated JAK/STAT signalling

Pharmacological Rac1 inhibitors with selective apoptotic activity in human acute leukemic cell lines

Rac1 GTPase-deficient HeLa cells present reduced DNA repair, proliferation, and survival under UV or gamma irradiation

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