PSP205, a Novel\nPhenyl Sulfonyl Piperidine, Induces\nApoptotic Cell Death in Colon Cancer by Modulating Coat Protein Complex-Mediated\nVesicle Trafficking

The\nendoplasmic reticulum (ER) stress and autophagic\npathways offer\nattractive targets for the development of new cancer drugs. Here,\nwe identified a novel phenyl sulfonyl piperidine, PSP205, that induces\nprolonged ER-stress-mediated autophagy and apoptosis in colon cancer\ncells. Transcriptome analysis of cells exposed to PSP205 unveiled\ntranscriptional upregulation of genes associated with the ER stress\nresponse or unfolded protein response (UPR), in addition to vesicle\ntransport. Among the top upregulated genes, DNAJB9, XBP1, PDIA4, HSPA5,\nSEC24D, and SEC11C are implicated in ER stress. Gene set enrichment\nanalysis revealed the enrichment of gene sets involved in the UPR,\nmTORC1 signaling, hypoxia, the P53 pathway, apoptosis, and the ER–Golgi-vesicle-mediated\ntransport pathway. Mechanistic studies showed that PSP205 acts on\nthe IRE1-TRAF2-JNK pathway to modulate autophagic flux, leading to\nmacroautophagy, ER-phagy, and deformation of Golgi. Our study also\ndemonstrated that PSP205 decreases the expression of the COPI coat\ncomplex subunit beta 2 (COPB2) in the presence of COPB2 siRNA. Furthermore,\nPSP205 synergistically killed colon cancer cells in combination with\nproteasome and topoisomerase inhibitors. Cumulatively, our findings\nsuggest that PSP205 targets cancer cells via a novel mechanism, specifically\nby decreasing the level of COPB2, which has not been extensively studied\nin the context of cancer therapy development and warrants further\ninvestigation.