Phytochemical targeting of STAT3 orchestrated lipid metabolism in therapy-resistant cancers

Abstract

Lipids are critical for maintaining homeostasis and cellular metabolism. However, the dysregulation of lipid metabolism contributes to the pathogenesis of chronic inflammatory diseases and is a hallmark of several cancer types. Tumours exist in a microenvironment of poor vascularization-depleted oxygen and restricted nutrients. Under these conditions, tumours have been shown to increasingly depend on the metabolism of fatty acids for sustained proliferation and survival. Signal transducer and activator of transcription 3 (STAT3) plays a key role in cellular processes such as cell growth, apoptosis and lipid metabolism. Aberrant STAT3 activity, as seen in several cancer types, is associated with tumour progression and malignancy, in addition to propagating crosstalk between tumour cells and the microenvironment. Furthermore, STAT3-regulated lipid metabolism is critical for cancer stem cell self-renewal and therapy resistance. Plant-derived compounds known as phytochemicals are a potential source for novel cancer therapeutic drugs. Dietary phytochemicals are known to modulate key cellular signalling pathways involved in lipid homeostasis and metabolism, including the STAT3 signalling pathways. Targeting STAT3 orchestrated lipid metabolism has shown therapeutic promise in human cancer models. In this review, we summarize the antitumour activity of phytochemicals with an emphasis placed on their effect on STAT3-regulated lipid metabolism and their role in abrogating therapy resistance.