Hypertonicity-imposed BCL-XL addiction primes colorectal cancer cells for death

Heimer, Sina; Knoll, Gertrud; Steixner, Charlotte; Calance, Diana Nicoleta; Trinh, Dieu Thuy; Ehrenschwender, Martin

doi:10.1016/j.canlet.2018.07.035

Cited by 9 publications

(15 citation statements)

References 46 publications

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“…Moreover, there is evidence that increased extracellular Na + helps in antigen degradation [15] and fighting viral infections [16,17]. In addition, elevated Na + levels prime malignant cells for apoptosis [18,19] and augment the cytotoxic potential of death receptors in cancer cells [20]. However, the mechanism underlying enhanced antibacterial activity in MΦ is unclear.…”

Section: Introductionmentioning

confidence: 99%

HIF1A and NFAT5 coordinate Na⁺-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting

et al. 2019

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Infection and inflammation are able to induce diet-independent Na +-accumulation without commensurate water retention in afflicted tissues, which favors the pro-inflammatory activation of mouse macrophages and augments their antibacterial and antiparasitic activity. While Na +-boosted host defense against the protozoan parasite Leishmania major is mediated by increased expression of the leishmanicidal NOS2 (nitric oxide synthase 2, inducible), the molecular mechanisms underpinning this enhanced antibacterial defense of mouse macrophages with high Na + (HS) exposure are unknown. Here, we provide evidence that HS-increased antibacterial activity against E. coli was neither dependent on NOS2 nor on the phagocyte oxidase. In contrast, HS-augmented antibacterial defense hinged on HIF1A (hypoxia inducible factor 1, alpha subunit)-dependent increased autophagy, and NFAT5 (nuclear factor of activated T cells 5)-dependent targeting of intracellular E. coli to acidic autolysosomal compartments. Overall, these findings suggest that the autolysosomal compartment is a novel target of Na +modulated cell autonomous innate immunity.

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Section: Introductionmentioning

confidence: 99%

HIF1A and NFAT5 coordinate Na⁺-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting

et al. 2019

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“…This BH3-only protein determines sensitivity to BCL-XL targeting BH3 mimetics in various cancer entities 32,[38][39][40][41] . In previous work, we showed that hyperosmotic stress is capable to facilitate activation of the intrinsic apoptosis pathway [8][9][10]42 . However, in these studies we repeatedly failed to detect hypertonicity-induced disturbances in the BCL-2 protein family network.…”

Section: Discussionmentioning

confidence: 97%

“…In previous work, we showed that hyperosmotic stress facilitates MOMP induction [8][9][10] . Hyperosmotic stress (or hypertonicity) occurs when osmotically active solutes (such as NaCl) cannot passively diffuse across the plasma membrane and thus establish an osmotic pressure gradient between the extra-and intracellular space.…”

Section: Hyperosmotic Stress Renders Selective Bcl-xl Inhibition Suffmentioning

confidence: 91%

“…Preclinical studies demonstrated that inhibition of two or more BCL-2-like proteins was required to overcome this limitation [4][5][6][7] . Our previous work showed that cancer cells facing a hypertonic environment exhibited a lower threshold for MOMP induction [8][9][10] . We hypothesized that this could reflect hypertonicity-induced alterations in the BCL-2 family network.…”

Section: Introductionmentioning

confidence: 97%

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NOXA-dependent contextual synthetic lethality of BCL-XL inhibition and “osmotic reprogramming” in colorectal cancer

et al. 2020

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A sophisticated network of BCL-2 family proteins regulates the mitochondria-associated (intrinsic) apoptosis pathway. Antiapoptotic members such as BCL-XL or MCL-1 safeguard the outer mitochondrial membrane and prevent accidental cell death in a functionally redundant and/or compensatory manner. However, BCL-XL/MCL-1-mediated "dual apoptosis protection" also impairs response of cancer cells to chemotherapy. Here, we show that hyperosmotic stress in the tumor environment abrogates dual BCL-XL/MCL-1 protection. Hypertonicity triggers upregulation of NOXA and loss of MCL-1 and thereby enforces exclusive BCL-XL addiction. Concomitant targeting of BCL-XL is sufficient to unlock the intrinsic apoptosis pathway in colorectal cancer cells. Functionally, "osmotic reprogramming" of the tumor environment grants contextual synthetic lethality to BCL-XL inhibitors in dually BCL-XL/MCL-1-protected cells. Generation of contextual synthetic lethality through modulation of the tumor environment could perspectively boost efficacy of anticancer drugs.

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“…Cell viability was measured using MTT-based assays and has also been described in earlier studies [56,57]. Cells were seeded in 96-well plates (2 9 10 4 cells/well) and challenged with the indicated concentrations of the indicated substances in duplicates (technical replicates).…”

Section: Mtt-based Cell Viability Assaymentioning

confidence: 99%

Hypertonicity counteracts MCL‐1 and renders BCL‐XL a synthetic lethal target in head and neck cancer

et al. 2020

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Head and neck squamous cell carcinoma (HNSCC) is an aggressive and difficult-to-treat cancer entity. Current therapies ultimately aim to activate the mitochondria-controlled (intrinsic) apoptosis pathway, but complex alterations in intracellular signaling cascades and the extracellular microenvironment hamper treatment response. On the one hand, proteins of the BCL-2 family set the threshold for cell death induction and prevent accidental cellular suicide. On the other hand, controlling a cell's readiness to die also determines whether malignant cells are sensitive or resistant to anticancer treatments. Here, we show that HNSCC cells upregulate the proapoptotic BH3-only protein NOXA in response to hyperosmotic stress. Induction of NOXA is sufficient to counteract the antiapoptotic properties of MCL-1 and switches HNSCC cells from dual BCL-XL/MCL-1 protection to exclusive BCL-XL addiction. Hypertonicity-induced functional loss of MCL-1 renders BCL-XL a synthetically lethal target in HNSCC, and inhibition of BCL-XL efficiently kills HNSCC cells that poorly respond to conventional therapies. We identify hypertonicity-induced upregulation of NOXA as link between osmotic pressure in the tumor environment and mitochondrial priming, which could perspectively be exploited to boost efficacy of anticancer drugs. Abbreviations CI, combination index; EGFR, epidermal growth factor receptor; ER, endoplasmic reticulum; HNSCC, head and neck squamous cell carcinoma; OMM, outer mitochondrial membrane.

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Hypertonicity-imposed BCL-XL addiction primes colorectal cancer cells for death

Cited by 9 publications

References 46 publications

HIF1A and NFAT5 coordinate Na⁺-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting

HIF1A and NFAT5 coordinate Na⁺-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting

NOXA-dependent contextual synthetic lethality of BCL-XL inhibition and “osmotic reprogramming” in colorectal cancer

Hypertonicity counteracts MCL‐1 and renders BCL‐XL a synthetic lethal target in head and neck cancer

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Hypertonicity-imposed BCL-XL addiction primes colorectal cancer cells for death

Cited by 9 publications

References 46 publications

HIF1A and NFAT5 coordinate Na+-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting

HIF1A and NFAT5 coordinate Na+-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting

NOXA-dependent contextual synthetic lethality of BCL-XL inhibition and “osmotic reprogramming” in colorectal cancer

Hypertonicity counteracts MCL‐1 and renders BCL‐XL a synthetic lethal target in head and neck cancer

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HIF1A and NFAT5 coordinate Na⁺-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting

HIF1A and NFAT5 coordinate Na⁺-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting