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Lactate promotes resistance to glucose starvation via upregulation of Bcl-2 mediated by mTOR activation.

Oncology reports (2014-12-09)
Chen Huang, Shile Sheng, Rui Li, Xiaoguang Sun, Jianju Liu, Gang Huang
ABSTRACT

Solid tumors grow faster and need more glucose than normal tissue; however, due to poor angiogenesis and excessive growth, tumors remote from blood vessels are always under glucose starvation. Even so, cancer cells remain alive in vivo. Thus, making cancer cells sensitive to glucose depletion may potentially provide an effective strategy for cancer intervention. Tumors that obtain sufficient glucose generate a large amount of lactate. Therefore, we proposed that lactate, a tumor microenvironment factor, may allow cancer cells to develop resistance to glucose starvation-induced death. We cultured cancer cells in no-glucose medium and added lactate to the medium. During the experiment, lactate helped cancer cells to escape from glucose starvation-induced cell death, without using lactate as an energy substrate, resulting in activation of Akt through PI3K. Akt activation plays a central role in cell growth through the activation of mammalian target of rapamycin (mTOR). Alteration of the PI3K/Akt/mTOR signaling pathway by inhibiting apoptosis induced specific upregulation of B-cell lymphoma 2 (Bcl-2) through translational control. In conclusion, this study showed that lactate rescues cancer cells from glucose starvation-induced cell death through regulation of the PI3K/Akt/mTOR/Bcl-2 signaling pathway. These data suggest that lactate is an important determinant of the sensitivity of tumors to glucose starvation, and reducing lactate or inhibiting the PI3K/Akt/mTOR/Bcl-2 signaling pathway may influence the response of cancers to glucose starvation.

MATERIALS
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