Characterising the Response of Human Breast Cancer Cells to Polyamine Modulation

Abstract

Breast cancer is a complex heterogeneous disease with multiple underlying causes. The polyamines putrescine, spermidine, and spermine are polycationic molecules essential for cell proliferation. Their biosynthesis is upregulated in breast cancer and they contribute to disease progression. While elevated polyamines are linked to breast cancer cell proliferation, there is little evidence to suggest breast cancer cells of different hormone receptor status are equally dependent on polyamines. In this study, we characterized the responses of two breast cancer cells, ER+ (oestrogen receptor positive) MCF-7 and ER- MDA-MB-231 cell lines, to polyamine modulation and determined the requirement of each polyamine for cancer cell growth. The cells were exposed to DFMO (a polyamine pathway inhibitor) at various concentrations under different conditions, after which several growth parameters were determined. Exposure of both cell lines to DFMO induced differential growth responses, MCF-7 cells showed greater sensitivity to polyamine pathway inhibition at various DFMO concentrations than the MDA-MB-231 cells. Analysis of intracellular DFMO after withdrawal from growth medium showed residual DFMO in the cells with concomitant decreases in polyamine content, ODC protein level, and cell growth. Addition of exogenous polyamines reversed the cell growth inhibition, and this growth recovery appears to be partly dependent on the spermidine content of the cell. Similarly, DFMO exposure inhibits the global translation state of the cells, with spermidine addition reversing the inhibition of translation in the breast cancer cells. Taken together, these data suggest that breast cancer cells are differentially sensitive to the antitumour effects of polyamine depletion, thus, targeting polyamine metabolism might be therapeutically beneficial in breast cancer management based on their subtype.

Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition

“…This correlates with the immune suppression we see in our studies as well as the characterization of GBM as a "cold tumor" 38 . While our studies focused on GBM, polyamines have been reported to have a protumorigenic role in established tumors in other cancerssuch as prostate and colorectaland a tumor suppressive role at the initial stages in other tumorsnamely melanoma and some types of breast cancer [39][40][41][42][43] . Therefore, our findings may be of interest to other tumor types.…”

Microbial metabolites are involved in tumorigenesis and development by regulating immune responses

“…Numerous studies have demonstrated their involvement in the occurrence and development of colorectal inflammation and tumors (24)(25)(26)(27)(28)(29)(30). Additionally, the role of SCFAs in lung cancer (31), PAs in brain tumors and neuroblastoma (32, 33), SCFAs, MTCs and secondary bile acids in digestive system tumors (21,(34)(35)(36), and SCFAs, MTCs and PAs in gynecological tumors and melanoma (31,34,(37)(38)(39)(40)(41)(42) have also been confirmed. Therefore, this review focuses on the above five intestinal microbial metabolites.…”

Spermidine content of selected dietary supplements: potential for improvement?

“…Different effects may apply to cancer patients than to healthy individuals, especially during chemotherapy, but more research is needed [5][32]. Attempts to slow down tumor growth by inhibiting spermidine production have had little success and they have so far been limited to a few types of tumors, such as subtypes of breast cancer [33].…”