Downregulation of Xeroderma Pigmentosum Complementation Group C Expression by 17-Allylamino-17-Demethoxygeldanamycin Enhances Bevacizumab-Induced Cytotoxicity in Human Lung Cancer Cells

Abstract

<b><i>Introduction:</i></b> Xeroderma pigmentosum complementation group C (XPC) protein is an important DNA damage recognition factor involved in nucleotide excision repair and regulation of non-small-cell lung cancer (NSCLC) cell proliferation and viability. 17-Allylamino-17-demethoxygeldanamycin (17-AAG) blocks ATP binding to heat shock protein 90 (Hsp90), resulting in destabilization of Hsp90-client protein complexes. Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor expressed by many types of tumors. Bevacizumab (Avastin) is a humanized monoclonal antibody against human VEGF used as an antiangiogenesis agent in the therapy of many cancers, proving successful in increasing objective tumor response rate and prolonging overall survival in NSCLC patients. <b><i>Methods:</i></b> After the bevacizumab and/or 17-AAG treatment, the expressions of XPC mRNA were determined by quantitative real-time PCR analysis. Protein levels of XPC and phospho-AKT were determined by Western blot analysis. We used specific XPC small interfering RNA and PI3K inhibitor (LY294002) to examine the role of the AKT-XPC signal in regulating the chemosensitivity of bevacizumab and 17-AAG. Cell viability was assessed by the MTS assay and trypan blue exclusion assay. <b><i>Results:</i></b> In this study, bevacizumab decreased XPC expression in human lung squamous cell carcinoma H520 and H1703 cells via AKT inactivation. Enhancement of AKT activity by transfection with constitutively active AKT vectors increased XPC expression and cell survival after treatment with bevacizumab. In addition, 17-AAG synergistically enhanced bevacizumab-induced cytotoxicity and cell growth inhibition in H520 and H1703 cells, associated with downregulation of XPC expression and inactivation of AKT. <b><i>Discussion/Conclusion:</i></b> Together, these results may provide a rationale to combine bevacizumab with Hsp90 inhibitors in future to enhance therapeutic effects for lung cancer.

Identification and validation of a 9-gene signature for the prognosis of ovarian cancer by integrated bioinformatical analysis

“…The overexpression of MAD2L1 has been discovered in diverse malignancies, such as lung ( 24 ), breast ( 25 ), and gastric cancers ( 26 ). XPC has been identified as an essential protein that recognizes DNA damage and performs an integral function in the repair of nucleotide excision and the modulation of cell growth and viability in non-small cell lung cancer ( 27 ). EGLN3 regulates tumor cell apoptosis and proliferation in glioma ( 28 ).…”

XPC multifaceted roles beyond DNA damage repair: p53-dependent and p53-independent functions of XPC in cell fate decisions

“…By conducting germline and tumour whole-exome sequencing (WES) on 44 stage III/IV melanoma patients, Aoude et al demonstrated that XPC is one of the pathogenic germline variants associated with poor overall survival [95]. Furthermore, investigation of the role of XPC in anti-angiogenesis treatment of human non-small-cell lung cancer (NSCLC) [96] revealed that down-regulation of XPC by 17-allylamino-17demethoxygeldanamycin (17-AAG) enhanced the cytotoxic action of bevacizumab, a VEGF antibody that inhibits angiogenesis. It was concluded that downregulation of XPC levels A inhibits hypoxia-inducible factor 1 alpha (HIF-1α)-mediated transcription of XPC, thus downregulating XPC levels and overcoming hypoxia-induced cisplatin resistance [97].…”