Hypertonicity-enforced BCL-2 addiction unleashes the cytotoxic potential of death receptors

Abstract

Attempts to exploit the cytotoxic activity of death receptors (DR) for treating cancer have thus far been disappointing. DR activation in most malignant cells fails to trigger cell death and may even promote tumor growth by activating cell death-independent DR-associated signaling pathways. Overcoming apoptosis resistance is consequently a prerequisite for successful clinical exploitation of DR stimulation. Here we show that hyperosmotic stress in the tumor microenvironment unleashes the deadly potential of DRs by enforcing BCL-2 addiction of cancer cells. Hypertonicity robustly enhanced cytotoxicity of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and other DR ligands in various cancer entities. Initial events in TRAIL DR signaling remained unaffected, but hypertonic conditions unlocked activation of the mitochondrial death pathway and thus amplified the apoptotic signal. Mechanistically, we demonstrate that hyperosmotic stress imposed a BCL-2-addiction on cancer cells to safeguard the integrity of the outer mitochondrial membrane (OMM), essentially exhausting the protective capacity of BCL-2-like pro-survival proteins. Deprivation of these mitochondrial safeguards licensed DR-generated truncated BH3-interacting domain death agonist (tBID) to activate BCL-2-associated X protein (BAX) and initiated mitochondrial outer membrane permeabilization (MOMP). Our work highlights that hyperosmotic stress in the tumor environment primes mitochondria for death and lowers the threshold for DR-induced apoptosis. Beyond TRAIL-based therapies, our findings could help to strengthen the efficacy of other apoptosis-inducing cancer treatment regimens.

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

“…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.…”

Death receptor 5 is activated by fucosylation in colon cancer cells

“…However, Mapatumumab (HGS‐ETR1), TRAIL‐R1 agonistic antibody, in Phase II clinical trial did not show satisfactory activity with refractory colorectal cancer patients . This was shown due to the resistance of colorectal cancer cell lines to TRAIL . The current focus is to use the combination strategies to overcome TRAIL resistance.…”

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

“…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.…”

“…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.…”

“…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.…”