Axl Promotes Cutaneous Squamous Cell Carcinoma Survival through Negative Regulation of Pro-Apoptotic Bcl-2 Family Members

Abstract

Expression of Axl, a receptor tyrosine kinase, is increased in cutaneous squamous cell carcinoma (SCC). Examination of a series of cutaneous SCC tumors revealed positive phospho-Akt (P-Akt) staining accompanied by weak TUNEL staining in Axl-positive tumors, suggesting an anti-apoptotic role for Axl in SCC survival. The role of Axl in UV-induced apoptosis was investigated in a cutaneous SCC cell line using retroviral short hairpin RNA sequences enabling stable Axl knock-down. We show that, although Axl knock-down has no effect on cell proliferation, it sensitizes cells to UV-induced apoptosis through increased activation of the pro-apoptotic protein Bad, a change in the conformation of Bax and Bak, release of cytochrome c into the cytosol, and activation of caspases. These events are accompanied by faster Akt dephosphorylation in UV-treated Axl knock-down cells and correlate with the degree of Axl knock-down. Treatment with the pan-caspase inhibitor zVAD-fmk partially rescued cells from UV-induced apoptosis but did not affect Bid cleavage or cytochrome c release, suggesting that cells die via the mitochondrial-mediated pathway. Thus, Axl confers resistance of SCC cells to apoptosis and displays potential as a target for therapeutic intervention in cutaneous SCC.

Macrophage–tumor crosstalk: role of TAMR tyrosine kinase receptors and of their ligands

“…3). Activation of Axl induces proliferation [149,150], survival [151][152][153][154], resistance against apoptosis [151,155,156], migration and invasiveness of cancer cells [149][150][151][152][153][154]. Furthermore, Axl mediates resistance towards chemo-and targeted therapy including anti-VEGF or anti-EGFR therapy in part by inducing secretion of proinflammatory and protumoral cytokines such as IL-6, TNFa and G-CSF in TAMs, where it is highly expressed [157].…”

Gas6/Axl Inhibits Osteosarcoma Apoptosis through Regulation of Apoptosis-Related Protein Bcl-2

“…Extrinsic pathway which is triggered through death receptors and intrinsic one which is caused by mitochondrial alterations. In the extrinsic pathway, cell death depends on amounts of various members of Bcl2 family [22]. On the other hand, targeting the AKT/GSK3β/cyclin D1/Cdk4 pathway can be an efficient modality to suppress cell cycle to acquire radio resistance of tumor cells [23,24].…”

“…However, studies on the exact inhibition of apoptosis by Axl and the anti-apoptotic mechanisms in osteosarcoma have been rarely reported [21]. ES Papadakis et al have confirmed that Axl could negatively regulate pro-apoptotic Bcl-2 family members and promote cellular survival in cutaneous squamous cell carcinoma [22]. It is interesting to determine whether there is a similar mechanism for Axl to control apoptosis in osteosarcoma.…”

Tiroid Kanserinde Tirozin Kinaz İnhibitörleri: Axl/Gas6 Yolağı Gizli Bir Hedef Olabilir mi?

“…39 The same applies to Nilotinib. 40 Axl overexpression and/or activation has been related to resistance to chemotherapy in some other cancer types ; gastrointestinal stromal tumor cell lines 41 , rhabdomyosarcoma 42 , HER-2 positive breast tumor cells 43 , cutaneous squamous cell carcinoma (SCC) 44 , Kaposi sarcoma 45 and ovarian cancer. 46 Drugs targeting Axl are currently under investigation.…”