Inhibition of Heme Export and/or Heme Synthesis Potentiates Metformin Anti-Proliferative Effect on Cancer Cell Lines

SIMPLE SUMMARY: Tumor initiation and progression are sustained by the ability of the cancer cell to reshape its metabolism in a way that favors cell proliferation and survival. Recently, it was shown that heme metabolism contributes to metabolic adaptation of tumor cell and that interfering with heme homeostasis reduces tumor cell growth. Here, we show that the alteration of heme metabolism, either by RNA-interference or pharmacological approaches, increases the sensitivity of tumor cell lines to the antitumor agent metformin. These findings strengthen the concept of targeting heme metabolism to counteract tumor progression. ABSTRACT: Cancer is one of the leading causes of mortality worldwide. Beyond standard therapeutic options, whose effectiveness is often reduced by drug resistance, repurposing of the antidiabetic drug metformin appears promising. Heme metabolism plays a pivotal role in the control of metabolic adaptations that sustain cancer cell proliferation. Recently, we demonstrated the existence of a functional axis between the heme synthetic enzyme ALAS1 and the heme exporter FLVCR1a exploited by cancer cells to down-modulate oxidative metabolism. In colorectal cancer cell lines, the inhibition of heme synthesis-export system was associated with reduced proliferation and survival. Here, we aim to assess whether the inhibition of the heme synthesis-export system affects the sensitivity of colorectal cancer cells to metformin. Our data demonstrate that the inhibition of this system, either by blocking heme efflux with a FLVCR1a specific shRNA or by inhibiting heme synthesis with 5-aminolevulinic acid, improves metformin anti-proliferative effect on colorectal cancer cell lines. In addition, we demonstrated that the same effect can be obtained in other kinds of cancer cell lines. Our study provides an in vitro proof of concept of the possibility to target heme metabolism in association with metformin to counteract cancer cell growth.