Fig 2: BH3 profiling determines that mitochondrial priming is dependent on BCLXL in 5-fluorouracil (5-FU)-resistant HT-29 cells. (A) Heat map for mitochondrial responses to nine BH3 peptides in three colon cancer cell lines of both parental and 5-FU-resistant cells. Bar graph representing the percentage of mitochondrial depolarization in parental and 5-FU-resistant HT-29 cells when treated with BAD (B), PUMA (C), BMF (D), HRK (E) and XXA1 (F). All data represent the mean ± SD (n=3). *P<0.01, a significant difference when compared to parental HT-29 cells.

Fig 3: The mechanism of KPNB1 inhibition-induced apoptosis in glioblastoma cells. KPNB1 inhibition results in cytosolic localization of its cargos, which perturbs proteostasis and activates both UPR and protein degradation pathways to relieve protein overload. Blockade of protein degradation by inhibitors of proteasome or lysosome aggravates accumulation of ubiquitinated proteins and potentiates IPZ-induced apoptosis, whereas blockade of protein synthesis by inhibitors of translation or transcription has opposite effects. Failure of proteostasis recovery sustained activates eIF2α/ATF4 signaling, which upregulates BH3-only proteins and induces adaptive autophagy. Noxa and/or Puma compromise the binding of Mcl-1 and/or Bcl-xL to Bax and Bak, thus promoting apoptosis that can be enhanced by Bcl-xL inhibitors

Fig 4: Delanzomib enhances Dox‐induced apoptosis via p53 stabilization, p21, p27, PUMA, and NOXA upregulation, and p38/JNK activation in breast cancer cells. Four breast cancer cell lines (MCF‐7, MDA‐MB‐361, MDA‐MB‐231, and HCC‐1954) which represent the four major molecular subtypes of breast cancer, were cultured with Dox (0.05 μM) alone or in combination with delanzomib (0.1 μM) for 6, 8, or 12 hours. Untreated cells were used as controls. Whole‐cell lysates were subjected to sodium dodecyl sulfate‐polyacrylamide gel electrophoresis and immunoblotted with indicated antibodies. α‐tublin was used as a loading control.

Fig 5: Gene expression profiling revealed the relationship between the expression of C1QTNF6 and ID1, BBC3, DDIT3. A The enrichment of genes with significantly different expression in diseases and functions. The abscissa is the disease or the function name, and the ordinate is the significance level of − log (10) value for enrichment. B Disease and Function Heat Map illustrates the relationships between the differentially expressed genes and functions and diseases. C Interaction network of several molecules closely connected to C1QTNF6, as determined by IPA. D Western blot assay showing the expression of ID1, JAK2, DDIT3, MKI67, and BBC3 transfected with Ctrl-shRNA or C1QTNF6-shRNA. Data is represented as mean ± SD, *P < 0.05