Fig. 2: Impacts of AA exposure on sunitinib therapeutic outcomes.

a Kaplan–Meier curves of progression-free survival (PFS) for patients with (n = 19) or without (n = 94) the AA signature (two-sided GB-Wilcoxon test). b Comparisons of tumor size between patients with (n = 19) or without (n = 94) the AA signature (two-sided t-test). Data were shown as mean ± SD. c Pathways enriched by differentially expressed proteins between patients with or without the AA signature. d Left panel: heatmap showed the expression of glycolysis-related and PPP-related proteins at the transcriptome and proteome levels, respectively. The values were transformed by z-score. Right panel: Glucose metabolism alteration caused by the AA signature. e, f Proliferation of 786 O and ACHN cells was detected by CCK-8 assay (AA-100 μM, Sunitinib-200 nM, n = 9 independent experiments, two-sided t-test). P values were described in the figure. ns not significant. Shown are the average values with SD. g, h AA treatment inhibited the expressions of G6PD, PGD, and TKT in 786 O and ACHN cells in time-and dose-dependent manners. Numerical values below the gels indicate the quantification of the bands relative to the control (hereinafter). i Ribose-5-phosphate concentrations in cells treated with AA or not (n = 3 independent experiments, two-sided t-test). Data were shown as mean ± SD. P values were described in the figure. J, k Left panel, SP1 knockdown downregulated PPP enzymes at the protein level. Right panel, SP1 overexpression upregulated PPP enzymes at the protein level, in 786 O and ACHN cells, respectively. Numerical values below the gels indicate the quantification of the bands relative to the control. l, m AA treatment did not affect the transcription of SP1 in the 786-O cell and ACHN cell, respectively (n = 3 independent experiments). Data were shown as mean ± SD. (AA-100 μM, 24 h). n MG132 abrogated the AA-mediated PPP enzymes downregulation by inhibiting the degradation of SP1. (AA-100 μM, 24 h). Numerical values below the gels indicate the quantification of the bands relative to the control. o Schematic diagram showing AA regulated the pentose phosphate pathway. Source data are provided as a Source Data file.