Hypertonicity primes malignant melanoma cells for apoptosis

Abstract

The tumor environment critically influences responsiveness of cancer cells to chemotherapies, most of which activate the mitochondria-regulated (intrinsic) apoptotic cascade to kill malignant cells. Especially skin tumors encounter an environment with remarkable biophysical properties. Cutaneous accumulation of Na locally establishes osmotic pressure gradients in vivo (hypertonicity or hyperosmotic stress), but whether cutaneous hypertonicity is a factor that modulates the responsiveness of skin cancers to therapeutic apoptosis-induction has thus far not been investigated. Here, we show that hyperosmotic stress lowers the threshold for apoptosis induction in malignant melanoma, the deadliest form of skin cancer. Hypertonic conditions enforce addiction to BCL-2-like proteins to prevent initiation of the mitochondria-regulated (intrinsic) apoptotic pathway. Essentially, hyperosmotic stress primes mitochondria for death. Our work identifies osmotic pressure in the tumor microenvironment as a cell extrinsic factor that modulates responsiveness of malignant melanoma cells to therapy.

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.…”

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.…”

Non-Apoptotic Cell Death Signaling Pathways in Melanoma

“…Other signaling pathways [25], melanoma-specific transcriptional regulators [26] and post-transcriptional control [27] also extensively contribute to the capability of melanoma cells to counteract unfavorable conditions, including exposition to anti-cancer therapies. In addition, microenvironment-mediated regulation of expression of pro-survival molecules, including MCL-1, BCL-X L , and BFL-1 [28][29][30], supports a remarkable adaptive capabilities of melanoma cells. Despite a tremendous advances in the therapeutic options for melanoma patients (Figure 1), inability or limited vulnerability of melanoma cells to induction of apoptosis in response to inhibitors of BRAF mut (BRAFi) and MEK (MEKi) [31][32][33][34][35][36][37][38], and escape from immunotherapy [39][40][41] are the reasons for re-growth of drug-resistant disease.…”