Inhibition of AXL enhances chemosensitivity of human ovarian cancer cells to cisplatin via decreasing glycolysis

Tian, Mingyi; Chen, Xisha; Li, Lan-ya; Wu, Hai-zhou; Zeng, Da; Wang, Xinluan; Zhang, Yi; Xiao, Songshu; Cheng, Yan

doi:10.1038/s41401-020-00546-8

Cited by 28 publications

(19 citation statements)

References 47 publications

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“…It has been reported that the overexpression of AXL can induce mitogen-activated protein kinase (MAPK) and triggering therapy resistance [231]. In ovarian cancer cells, decreasing AXL expression is correlated with CP sensitivity by suppressing glycolysis [232]. A combination of CP and pemetrexed can sufficiently stimulate cell death in mesothelioma cells via enhancing ROS levels.…”

Section: Therapeutic Targetingmentioning

confidence: 99%

Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies

et al. 2021

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The failure of chemotherapy is a major challenge nowadays, and in order to ensure effective treatment of cancer patients, it is of great importance to reveal the molecular pathways and mechanisms involved in chemoresistance. Cisplatin (CP) is a platinum-containing drug with anti-tumor activity against different cancers in both pre-clinical and clinical studies. However, drug resistance has restricted its potential in the treatment of cancer patients. CP can promote levels of free radicals, particularly reactive oxygen species (ROS) to induce cell death. Due to the double-edged sword role of ROS in cancer as a pro-survival or pro-death mechanism, ROS can result in CP resistance. In the present review, association of ROS with CP sensitivity/resistance is discussed, and in particular, how molecular pathways, both upstream and downstream targets, can affect the response of cancer cells to CP chemotherapy. Furthermore, anti-tumor compounds, such as curcumin, emodin, chloroquine that regulate ROS and related molecular pathways in increasing CP sensitivity are described. Nanoparticles can provide co-delivery of CP with anti-tumor agents and by mediating photodynamic therapy, and induce ROS overgeneration to trigger CP sensitivity. Genetic tools, such as small interfering RNA (siRNA) can down-regulate molecular pathways such as HIF-1α and Nrf2 to promote ROS levels, leading to CP sensitivity. Considering the relationship between ROS and CP chemotherapy, and translating these findings to clinic can pave the way for effective treatment of cancer patients.

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Section: Therapeutic Targetingmentioning

confidence: 99%

Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies

et al. 2021

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“…A2780/DDP is a cisplatin resistant strain of the A2780 cell line. Therefore, the A2780/DDP cell line is often used in the study of platinum-resistant ovarian cancer models [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

An Experimentally Induced Mutation in the UBA Domain of p62 Changes the Sensitivity of Cisplatin by Up-Regulating HK2 Localisation on the Mitochondria and Increasing Mitophagy in A2780 Ovarian Cancer Cells

Yan

Tian

et al. 2021

IJMS

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The study of cisplatin sensitivity is the key to the development of ovarian cancer treatment strategies. Mitochondria are one of the main targets of cisplatin, its self-clearing ability plays an important role in determining the fate of ovarian cancer cells. First, we proved that the sensitivity of ovarian cancer cells to cisplatin depends on mitophagy, and p62 acts as a broad autophagy receptor to regulate this process. However, p62′s regulation of mitophagy does not depend on its location on the mitochondria. Our research shows that the mutation of the UBA domain of p62 increases the localisation of HK2 on the mitochondria, thereby increasing the phosphorylated ubiquitin form of parkin, then stabilising the process of mitophagy and ultimately cell survival. Collectively, our results showed that a mutation in the UBA domain of p62 regulates the level of apoptosis stimulated by cisplatin in ovarian cancer.

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“…Some cancers are more prone to chemoresistance than others and increased frequency of chemoresistance often goes hand in hand with a poorer prognosis. This, for instance, is the case for ovarian cancer, in which resistance to the first-line platinum-based chemotherapeutics is very common [ 13 , 59 ]. The chemoresistance against platins in ovarian cancer has been shown to be mediated by Axl by different mechanisms.…”

Section: Axlmentioning

confidence: 99%

“…Therefore, this could indicate a pretarget resistance mechanism, as per classification of platinum resistance mechanisms by Galluzzi et al [ 60 ]. Additionally, Axl has been implied in an off-target resistance mechanism against cisplatin: Axl seems to increase aerobic glycolysis of ovarian cancer cells, also known as the Warburg effect [ 59 ]. Specifically, Axl was shown to phosphorylate the pyruvate kinase isoform PKM2 at tyrosine 105, which favors ATP production by aerobic glycolysis over the Krebs cycle.…”

Section: Axlmentioning

confidence: 99%

TAM Receptor Inhibition–Implications for Cancer and the Immune System

Aehnlich

Powell

Peeters

et al. 2021

Cancers

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Tyro3, Axl and MerTK (TAM) receptors are receptor tyrosine kinases which play important roles in efferocytosis and in the balancing of immune responses and inflammation. TAM receptor activation is induced upon binding of the ligands protein S (Pros1) or growth arrest-specific protein 6 (Gas6) which act as bridging molecules for binding of phosphatidyl serine (PtdSer) exposed on apoptotic cell membranes. Upon clearance of apoptotic cell material, TAM receptor activation on innate cells suppresses proinflammatory functions, thereby ensuring the immunologically silent removal of apoptotic material in the absence of deleterious immune responses. However, in T cells, MerTK signaling is costimulatory and promotes activation and functional output of the cell. MerTK and Axl are also aberrantly expressed in a range of both hematological and solid tumor malignancies, including breast, lung, melanoma and acute myeloid leukemia, where they have a role in oncogenic signaling. Consequently, TAM receptors are being investigated as therapeutic targets using small molecule inhibitors and have already demonstrated efficacy in mouse tumor models. Thus, inhibition of TAM signaling in cancer cells could have therapeutic value but given the opposing roles of TAM signaling in innate cells and T cells, TAM inhibition could also jeopardize anticancer immune responses. This conflict is discussed in this review, describing the effects of TAM inhibition on cancer cells as well as immune cells, while also examining the intricate interplay of cancer and immune cells in the tumor microenvironment.

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Inhibition of AXL enhances chemosensitivity of human ovarian cancer cells to cisplatin via decreasing glycolysis

Cited by 28 publications

References 47 publications

Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies

Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies

An Experimentally Induced Mutation in the UBA Domain of p62 Changes the Sensitivity of Cisplatin by Up-Regulating HK2 Localisation on the Mitochondria and Increasing Mitophagy in A2780 Ovarian Cancer Cells

TAM Receptor Inhibition–Implications for Cancer and the Immune System

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