Induction of Autophagy and Apoptosis in Triple‐Negative Breast Cancer Cells by LT‐IIc, a Type II Heat‐Labile Enterotoxin

Despite the recent advances in breast cancer treatment, triple negative breast cancer (TNBC) remains a serious health problem with poor prognosis and limited therapeutic options. Although hampered by development of resistance, chemotherapy‐based regimens remain the first‐line adjuvant choice for the treatment of TNBC. To combat development of resistance, it is essential to identify agents that induce cell death by independent induction of multiple cell death pathways. In this report, we screened cholera toxin (CT), a type I heat‐labile enterotoxin (HLT) of Vibrio cholerae , and LT‐IIa and LT‐IIb, type II HLT of Escherichia coli , for capacity to induce cell death specifically in triple‐negative MDA‐MB‐231 breast cancer cells. While CT, LT‐IIa and LT‐IIb had little effect on the cells, LT‐IIc reduced cell viability by ~50%, concomitant with development of extensive intracellular vacuolation. LT‐IIc‐induced cytotoxicity was not observed in MCF10A, a non‐tumorigenic breast epithelial cell line, or in MCF7, an estrogen receptor‐positive breast cancer cell line. LT‐IIc independently and simultaneously stimulated autophagy and apoptosis in MDA‐MB‐231 cells. Neither knockdown of ATG5, a key mediator of cellular autophagy, nor activation of caspase 3/7 disrupted LT‐IIc‐mediated cell death. Similarly, pharmacological disruption of autophagy using bafilomycin A1, did not interfere with LT‐IIc‐mediated cell death. In contrast, treatment of MDA‐MB‐231 cells with rapamycin, a known inducer of autophagy, enhanced LT‐IIc mediated cell death. Collectively, these findings indicate that LT‐IIc uniquely induces cell death through the divergent induction of autophagy and autophagy‐independent apoptotic pathways. Support or Funding Information D'Youville College School of Pharmacy and NIH