Gas6/Axl is the sensor of arginine-auxotrophic response in targeted chemotherapy with arginine-depleting agents

Tsai, Wen-Bin; Long, Yan; Park, Jeong-Ran; Chang, Jeffrey T.; Liu, Hui; Rodriguez‐Canales, Jaime; Savaraj, Niramol; Feun, Lynn G.; Davies, Michael A.; Wistuba, Ignacio I.; Kuo, M. Tien

doi:10.1038/onc.2015.237

Cited by 21 publications

(35 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Akt1 targeting impaired hydrogen-peroxide induced migration and inhibited Rac1 activation, suggesting redox regulation in Axl-related malignant cell migration [53]. In addition, ROS-mediated Gas6 secretion has been reported as an early event of arginine auxotrophic response in cancer cells, where the auxotrophic challenge provides PI3K/Akt pathway activation and c-Myc protein stabilization as well as myc transcriptional induction, further supporting feedback mechanisms to enhance Axl expression [54].…”

Section: Regulation Of Cell Aggressivenessmentioning

confidence: 91%

Role of the Receptor Tyrosine Kinase Axl and its Targeting in Cancer Cells

Corno

Gatti

Lanzi

et al. 2016

CMC

View full text Add to dashboard Cite

Aberrant expression and activation of receptor tyrosine kinases (RTK) is a frequent feature of tumor cells that may underlie tumor aggressiveness. Among RTK, Axl, a member of the Tyro3-Axl-Mer family, represents a potential therapeutic target in different tumor types given its over-expression which leads to activation of oncogenic signaling promoting cell proliferation and survival, as well as migration and invasion. Axl can promote aggressiveness of various cell types through PI3K/Akt and/or MAPK/ERK, and its expression can be transcriptionally regulated by multiple factors. Deregulated Axl expression and activation have been shown to be implicated in reduced sensitivity of tumor cells to target-specific and conventional antitumor agents, but the precise mechanism underlying these phenomena are still poorly understood. Several small molecules acting as Axl inhibitors have been reported, and some of them are undergoing clinical investigation. In this review, we describe Axl biological functions, its expression in cancer and in drug-resistant tumor cells and the development of inhibitors tailored to this receptor tyrosine kinase.

show abstract

Section: Regulation Of Cell Aggressivenessmentioning

confidence: 91%

Role of the Receptor Tyrosine Kinase Axl and its Targeting in Cancer Cells

Corno

Gatti

Lanzi

et al. 2016

CMC

View full text Add to dashboard Cite

show abstract

“…Autophagy was the first stress response described in arginine-starved tumor cells [27,29,65,66] (Fig. 3).…”

Section: Stress Responses Upon Adi-based Therapy -Autophagy Senescenmentioning

confidence: 99%

“…In some tumors, such as malignant melanomas, ASS1 promoter repression is a result of enhanced hypoxia-inducible factor-1 alpha (HIF1a) activity [28]. ASS1 expression is controlled by c-Myc and HIF-1α interacting with an E-box element located at the ASS1 gene promoter [29] (Fig. 3).…”

Section: Arginine Auxotrophy In Human Malignanciesmentioning

confidence: 99%

Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies

Riess

Shokraie

Classen

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Arginine auxotrophy occurs in certain tumor types and is usually caused by the silencing of argininosuccinate synthetase 1 or arginine lyase genes. Such tumors are often associated with an intrinsic chemoresistance and thus a poor prognosis. Arginine auxotrophy however renders these tumors vulnerable to treatment with arginine-degrading enzymes. Among the most frequently applied arginine-degrading agents are bacterial arginine deiminases (ADI). The anti-cancerous effects of ADI derived from different bacteria were extensively studied in numerous preclinical cell culture and xenograft models. Mycoplasma-derived ADI-PEG20 is most commonly used and is currently under clinical investigation as a single agent therapeutic as well as in combination with different antineoplastic compounds. Mechanistically, ADI is capable of reducing metabolic activity in tumor cells, contributing to autophagy, senescence and apoptosis in arginine auxotrophic cells. Although clinical trials are promising, the resistance development upon initial treatment response is an increasing challenge. Furthermore, interference of ADI with the tumor microenvironment is poorly understood. In the present review, we outline recent experimental ADI-based treatment approaches and their translation into the clinic. Furthermore, we summarize new insights into the molecular mechanisms underlying the anti-cancer effects of ADI that might facilitate the refinement of ADI-based combination therapy approaches.

show abstract

“…Gas6 and its receptors are expressed in macrophages, granulocytes, dendritic cells, and endothelial cells and vascular smooth muscle. Gas6 works by stimulating phagocytosis, reducing the inflammatory response, limiting hypoxic cell damage, and enhancing cell proliferation [13][14][15][16][17][18][19][20][21] . Gas6 activation of the TAM receptor produces meaningful therapeutic targets in thromboembolic diseases, atherosclerosis, sepsis, autoimmune diseases, and cancer 22,23 .…”

Section: ■ Discussionmentioning

confidence: 99%