Caveolae-Associated Molecules, Tumor Stroma, and Cancer Drug Resistance: Current Findings and Future Perspectives

Abstract

The discovery of small, “cave-like” invaginations at the plasma membrane, called caveola, has opened up a new and exciting research area in health and diseases revolving around this cellular ultrastructure. Caveolae are rich in cholesterol and orchestrate cellular signaling events. Within caveola, the caveola-associated proteins, caveolins and cavins, are critical components for the formation of these lipid rafts, their dynamics, and cellular pathophysiology. Their alterations underlie human diseases such as lipodystrophy, muscular dystrophy, cardiovascular disease, and diabetes. The expression of caveolins and cavins is modulated in tumors and in tumor stroma, and their alterations are connected with cancer progression and treatment resistance. To date, although substantial breakthroughs in cancer drug development have been made, drug resistance remains a problem leading to treatment failures and challenging translation and bench-to-bedside research. Here, we summarize the current progress in understanding cancer drug resistance in the context of caveola-associated molecules and tumor stroma and discuss how we can potentially design therapeutic avenues to target these molecules in order to overcome treatment resistance.

Alteration of cholesterol distribution at the plasma membrane of cancer cells: From evidence to pathophysiological implication and promising therapy strategy

“…Simply, decreased ER chol levels activate sterol regulatory element binding proteins (SREBPs) that increase the transcription of genes involved in chol synthesis and import into cells. Conversely, increased intracellular chol levels activate another nuclear receptor system, the liver X receptors (LXRs) which facilitate chol export (Tontonoz and Mangelsdorf 2003;Goldstein et al, 2006;Ikonen 2008;Goedeke and Fernandez-Hernando 2012;Luo et al, 2020). This section will give a simplified overview of the complex protein network that regulates these different stages of chol homeostasis (Figure 1A).…”

“…The chol biosynthetic pathway is tightly regulated by three key players, i.e. SREBP2, which regulates the transcription of genes encoding cholesterologenic enzymes, and HMGCR and squalene monooxygenase, two rate-limiting enzymes of the biosynthetic pathway [reviewed in (Brown and Goldstein 1997;Burg and Espenshade 2011;Chua et al, 2020;Luo et al, 2020)].…”

“…Excess chol is exported to the blood via ATP-binding cassette (ABC) subfamily A member 1 (ABCA1) or ABC subfamily G member 1 (ABCG1) to lipid-poor apolipoprotein A-I (ApoA-I), generating high-density lipoproteins (HDLs) (Gelissen et al, 2006;Rosenson et al, 2012;Daniil et al, 2013;Phillips 2014). Chol can also be exported to the intestinal lumen and bile ducts via ABCG5 and ABCG8 heterodimer (Luo et al, 2020). Nuclear receptor system LXRs are important regulators of chol export.…”

“…Therefore, its homeostasis must be tightly regulated as any disbalance could lead to cancer development. The metabolism of chol, trafficking and its related intracellular functions have been the subject of many investigation over the years (Ikonen 2008;Afonso et al, 2018;Luo et al, 2020). However, despite several years of research, whether this lipid plays a role in oncogenesis is still an open question.…”

Remarkable Effect of Increasing Glutamine Metabolism on Caveolin-1 in Breast Cancer: A Brief Report

“…However, the effect of glutamine metabolism on loss of CAV-1 has not been completely clari ed. Moreover, several articles con rmed the loss of caveoline-1 in cancer stroma and its poor clinical outcome (9)(10)(11), but the status of CAV-1 in breast cancer cells is still controversial. To obtain more insight into this issue, we studied the relationship between increased glutamine and loss of CAV-1, as well as evaluating therapeutic effect of metformin.…”