Key events in cancer: Dysregulation of SREBPs

Abstract

Lipid metabolism reprogramming is an important hallmark of tumor progression. Cancer cells require high levels of lipid synthesis and uptake not only to support their continued replication, invasion, metastasis, and survival but also to participate in the formation of biological membranes and signaling molecules. Sterol regulatory element binding proteins (SREBPs) are core transcription factors that control lipid metabolism and the expression of important genes for lipid synthesis and uptake. A growing number of studies have shown that SREBPs are significantly upregulated in human cancers and serve as intermediaries providing a mechanistic link between lipid metabolism reprogramming and malignancy. Different subcellular localizations, including endoplasmic reticulum, Golgi, and nucleus, play an indispensable role in regulating the cleavage maturation and activity of SREBPs. In this review, we focus on the relationship between aberrant regulation of SREBPs activity in three organelles and tumor progression. Because blocking the regulation of lipid synthesis by SREBPs has gradually become an important part of tumor therapy, this review also summarizes and analyzes several current mainstream strategies.

An Improved and Scalable Synthesis of the Potent SREBP Inhibitor KK-052 via [3+2] Cycloaddition

“…13 The allyl alcohol was converted to amine (9) by the Mitsunobu reaction and subsequent deprotection. Amidation using benzoyl chloride or m-toluoyl chloride and N,N,dimethylaminopyridine (DMAP) afforded the amide (5,6). To activate the amide bond, 5 or 6 was treated with oxalyl chloride in the presence of 2,6-lutidine to convert to benzimidoyl chloride (11 or 12).…”

“…1 Its mode of action involves inducing SREBP degradation akin to that of 25-hydroxyvitamin D3 [25(OH)D3], yet it operates independently of the vitamin D receptor (VDR) activity. [1][2][3] This distinctive attribute positions KK-052 as a promising candidate among potential therapeutics for addressing a spectrum of SREBPassociated disorders, encompassing metabolic diseases such as obesity, diabetes mellitus, dyslipidemia, hepatosteatosis, and atherosclerosis 4 as well as certain cancer types [5][6][7][8] (Figure 1). The activation of SREBP is implicated in lipid-driven cellular stress that leads to inflammation and fibrosis.…”

“…[2][3][4] This distinctive attribute positions KK-052 as a promising candidate among potential therapeutics for addressing a spectrum of SREBP-associated disorders, encompassing metabolic diseases such as obesity, diabetes mellitus, dyslipidemia, hepatosteatosis, and atherosclerosis, 5 as well as certain cancer types (Figure 1). [6][7][8][9] The activation of SREBP is implicated in lipid-driven cellular stress that leads to inflammation and fibrosis. 5,10 In-depth animal studies would require the gram-scale synthesis of KK-052.…”

Atherosclerosis, Diabetes Mellitus, and Cancer: Common Epidemiology, Shared Mechanisms, and Future Management

“…SREBPs are significantly upregulated in human cancers and mediate a mechanistic link between lipid metabolism reprogramming and malignancy [261]. SREBPs are activated in a lipid-independent manner in cancer by the PI3K/Akt/mTOR/SREBP1 signaling pathway, which is often abnormally activated in tumor cells.…”

SQLE is a promising prognostic and immunological biomarker and correlated with immune Infiltration in Sarcoma

“…[ 10 ] Dysregulation of the SREBP pathway has been associated with various diseases, including metabolic disorders and cancer. [ 11 ] SQLE has been implicated in the pathogenesis of several important diseases, including atherosclerosis and Alzheimer’s disease. Atherosclerosis is a chronic inflammatory disease of the arterial wall, characterized by the accumulation of lipids, inflammatory cells, and extracellular matrix components.…”