Transcriptional Basis of Ca 2+ Remodeling Reversal Induced by Polyamine Synthesis Inhibition in Colorectal Cancer Cells.

Colorectal cancer (CRC) is associated with mutations in APC/Wnt leading to c-myc activation and the overexpression of ODC1, the limiting step in polyamine synthesis. CRC cells also display a remodeling of intracellular Ca homeostasis that contributes to cancer hallmarks. As polyamines may modulate Ca homeostasis during epithelial tissue repair, we investigated whether polyamine synthesis inhibition may reverse Ca remodeling in CRC cells and, if so, the molecular basis for this reversal. To this end, we used calcium imaging and transcriptomic analysis in normal and CRC cells treated with DFMO, an ODC1 suicide inhibitor. We found that polyamine synthesis inhibition partially reversed changes in Ca homeostasis associated with CRC, including a decrease in resting Ca and SOCE along with an increased Ca store content. We also found that polyamine synthesis inhibition reversed transcriptomic changes in CRC cells without affecting normal cells. Specifically, DFMO treatment enhanced the transcription of SOCE modulators CRACR2A; ORMDL3; and SEPTINS 6, 7, 8, 9, and 11, whereas it decreased SPCA2, involved in store-independent Orai1 activation. Therefore, DFMO treatment probably decreased store-independent Ca entry and enhanced SOCE control. Conversely, DFMO treatment decreased the transcription of the TRP channels TRPC1 and 5, TRPV6, and TRPP1 while increasing TRPP2, thus probably decreasing Ca entry through TRP channels. Finally, DFMO treatment enhanced the transcription of the PMCA4 Ca pump and mitochondrial channels MCU and VDAC3 for enhanced Ca extrusion through the plasma membrane and mitochondria. Collectively, these findings suggested the critical role of polyamines in Ca remodeling in colorectal cancer.