Compared with U0126, the special MEK1/2 inhibitor, PD0325901 cannot halt cell ferroptotic cell death induced by FIN. But scientist and skeptics argued that the conclusion is unreliable because the MEK inhibitor U0126 was used in these above studies. And the overactive Ras-MEK pathway may enhance ROS generation via inhibiting cystine (Cys2) uptake or mitochondrial voltage-dependent anion channel 2/3 (VDAC 2/3) and consequently sensitize cancer cells to ferroptosis. The activation of Ras-mitogen-activated protein kinase (MEK) signaling can attribute to the sensitivity of cancer cells to ferroptosis, resulting from its promoting iron abundance in cancer by governing the expression levels of the transferrin receptor and ferritin. Moreover, it is still obscure that what kind of role P53-target genes take part in manipulating of the ferroptotic cell death ? The bidirectional regulation of ferroptosis by P53 in a cell-specific or context-dependent manner needs to be further investigated. These opposite jobs of p53 in operating the process of ferroptotic cell death were executed by different mechanisms, including effects on metabolic genes transcription, post-translational regulation or by virtue of P53-P21 axis. An argument does emerge that P53 expression may promote, limit, or detain the outset of ferroptosis in certain cells or conditions (Fig. Impressively, TP53 3KR can still hold the capacity of inhibiting tumorigenesis due to its ferroptosis induction. The acetylation-defective mutant TP53 3KR lost the ability to induce cell senescence, apoptosis, and cell-cycle arrest, which were the main functions of TP53 in tumor suppression. More clues for this role of ferroptosis can be derived from recent researches of the tumor suppressor P53 (TP53). Įmerging evidence implicated that ferroptosis may be an adaptive process which was critical for eradicating the carcinogenic cells.
Indeed, the ferroptosis inducer artesunate/erastin can promote ferroptosis in a Ras-reliant way in pancreatic cancer or transformed fibroblastic cells, while in a Ras-independent manner in leukemia cells. Some Ras WT cells including fibrosarcoma cells, kidney tubule cells, and T cells are vulnerable to erastin, but the RMS13 rhabdomyosarcoma cells with Ras mutation were resistant to erastin and RLS3. With the following studies, the relationship of Ras oncoprotein with ferroptosis becomes agnostic. Ferroptosis, from a cancer perspective: an overviewįerroptosis was first observed in oncogenic Ras-expressing human foreskin fibroblast cell line by a battery of small compounds considered as ferroptosis- inducing agents (FIN), including erastin and Ras-selective lethal small molecule 3 (RSL 3). The opportunity and challenge of cancer treatment based on ferroptosis will be detailed, which was desired to prosper new strategies for cancer therapy of clinical value. We herein review the occurrence and regulation of ferroptosis in various cancer cells. The underlying molecular mechanisms remain poorly understood. Although cancer cells are under continuous oxidative stress with an exquisite balance between thiols and catalytic iron, ferroptosis does not often happen in the cancer development. Studies have shown that the classic oxidative stress pathway was an important causative factor to induce ferroptosis. It plays a pivotal role in the depression of tumorigenesis by removing the cells that are deficient in key nutrients in the environment or damaged by infection or ambient stress. Ferroptosis is gradually accepted as an adaptive feature to eliminate the malignant cells. Researches indicated that ferroptosis could be triggered by diverse physiological conditions and pathological stresses in humans and animals.
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