Linking Late Endosomal Cholesterol with Cancer Progression and Anticancer Drug Resistance

Nguyen, Mai K. L.; Jose, Jaimy; Wahba, Mohamed; Bernaus-Esqué, Marc; Hoy, Andrew J.; Enrich, Carlos; Rentero, Carles; Grewal, Thomas

doi:10.3390/ijms23137206

Cited by 11 publications

(13 citation statements)

References 269 publications

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“…ANXA6 is the largest protein of all conserved annexins and is found primarily in the plasma membrane and endosomal compartments. ANXA6 acts as a multifunctional scaffold protein, recruiting signaling proteins, regulating cholesterol and membrane transport and influencing actin dynamics [ 11 – 15 ]. ANXA6 binds to specific membrane phospholipids in a Ca 2+ -dependent manner, providing a link between Ca 2+ signaling and membrane function.…”

Section: Introductionmentioning

confidence: 99%

ANXA6: a key molecular player in cancer progression and drug resistance

et al. 2023

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Annexin-A6 (ANXA6), a Ca2+-dependent membrane binding protein, is the largest of all conserved annexin families and highly expressed in the plasma membrane and endosomal compartments. As a multifunctional scaffold protein, ANXA6 can interact with phospholipid membranes and various signaling proteins. These properties enable ANXA6 to participate in signal transduction, cholesterol homeostasis, intracellular/extracellular membrane transport, and repair of membrane domains, etc. Many studies have demonstrated that the expression of ANXA6 is consistently altered during tumor formation and progression. ANXA6 is currently known to mediate different patterns of tumor progression in different cancer types through multiple cancer-type specific mechanisms. ANXA6 is a potentially valuable marker in the diagnosis, progression, and treatment strategy of various cancers. This review mainly summarizes recent findings on the mechanism of tumor formation, development, and drug resistance of ANXA6. The contents reviewed herein may expand researchers’ understanding of ANXA6 and contribute to developing ANXA6-based diagnostic and therapeutic strategies.

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Section: Introductionmentioning

confidence: 99%

ANXA6: a key molecular player in cancer progression and drug resistance

et al. 2023

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“…Anomalous lipid metabolism and signaling have been implicated in oncogenesis [4], and changes in tumor cholesterol metabolism are often associated with disease progression [5]. In general, cholesterol homeostasis is maintained by a balance between de novo biosynthesis, mainly regulated by 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), the uptake of exogenous low-density lipoprotein (LDL)-cholesterol by the LDL-receptor (LDLR), and esterification of endogenous as well as LDL-derived cholesterol by acetyl-CoA acetyltransferase 1 (ACAT-1).…”

Section: Introductionmentioning

confidence: 99%

“…In fact, targeting key cholesterol metabolic pathways in cancer cells slowed proliferation [6], migration/invasion, and tumor size in mouse models of BC [6,7,12]. Altered cholesterol metabolism has also been linked to the development of treatment resistance [5,13]. Evidence supporting this include reports that changes in cholesterol homeostasis coincide with the development of resistance to tamoxifen in luminal A BC [14] and in leukemic cell lines [15,16].…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin improves cisplatin sensitivity through modulation of cholesteryl ester homeostasis in breast cancer cells

et al. 2022

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Background Acquired treatment resistance is a significant problem in breast cancer management, and alterations in lipid metabolism have been proposed to contribute to the development of drug resistance as well as other aspects of tumor progression. The present study aimed to identify the role of cholesterol metabolism in MCF-7 and MDA-MB-231 breast cancer cell response to cisplatin (CDDP) treatment in the acute setting and in a model of CDDP resistance. Methods MCF-7 (luminal A), MDA-MB-231 (triple-negative) and CDDP-resistant MDA-MB-231 (MDACR) cell lines were grown in the presence or absence of CDDP in combination with atorvastatin (ATV), lipid depletion or low-density lipoprotein loading and were analyzed by a variety of biochemical and radiometric techniques. Results Co-administration of CDDP and ATV strongly reduced cell proliferation and viability to a greater extent than CDDP alone, especially in MDA-MB-231 cells. These findings were associated with reduced cholesteryl ester synthesis and storage in MDA-MB-231 cells. In MDACR cells, acetyl-CoA acetyltransferase 1 (ACAT-1) was upregulated compared to naïve MDA-MB-231 cells and ATV treatment restored CDDP sensitivity, suggesting that aberrant ACAT-1 expression and associated changes in cholesterol metabolism contribute to CDDP resistance in MDA-MB-231 cells. Conclusion These findings indicate that the elevated susceptibility of MDA-MB-231 cells to co-administration of CDDP and ATV, is associated with an increased reliance on cholesteryl ester availability. Our data from these cell culture-based studies identifies altered cholesterol homeostasis as an adaptive response to CDDP treatment that contributes to aggressiveness and chemotherapy resistance.

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“…Anomalous lipid metabolism and signaling have been implicated in oncogenesis (4) and changes in tumor cholesterol metabolism are often associated with disease progression (5). In general, cholesterol homeostasis is maintained by a balance between de novo biosynthesis, mainly regulated by 3-hydroxy-3methyl-glutaryl-coenzyme A reductase (HMGCR), the uptake of exogenous low-density lipoprotein (LDL)cholesterol by the LDL-receptor (LDLR), and esteri cation of endogenous as well as LDL-derived cholesterol by acetyl-CoA acetyltransferase 1 (ACAT-1).…”

Section: Introductionmentioning

confidence: 99%

“…In fact, targeting key cholesterol metabolic pathways in cancer cells slowed proliferation (6), migration/invasion, and tumor size in mouse models of BC (6,7,12). Altered cholesterol metabolism has also been linked to the development of treatment resistance (5,13). Speci cally, changes in cholesterol homeostasis coincide with the development of resistance to tamoxifen in luminal A BC (14), and leukemic cell lines (15,16).…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin Improves Cisplatin Sensitivity Through Modulation of Cholesteryl Ester Homeostasis in Breast Cancer Cells

Santos

Guimarães

Hakeem-Sanni

et al. 2022

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Background: Acquired treatment resistance is a major problem in breast cancer management. Alterations in lipid metabolism have been proposed to contribute to tumor progression and the development of drug resistance. The present study aimed to identify the role of cholesteryl ester (CE) metabolism in MCF-7 and MDA-MB-231 breast cancer cell line response to cisplatin (CDDP) treatment in the acute setting. Methods: MCF-7 (luminal A), MDA-MB-231 (triple-negative) and CDDP-resistant MDA-MB-231 (MDACR) cell lines were grown in the presence or absence of CDDP in combination with atorvastatin (ATV), lipid depletion or low-density lipoprotein (LDL) loading and were analyzed by a variety of biochemical and radiometric techniques. Results: Co-administration of CDDP and ATV strongly reduced cell proliferation and viability to a greater extent than CDDP alone, especially in MDA-MB-231 cells. These findings were associated with reduced CE synthesis and storage in MDA-MB-231 cells. In MDACR cells, acetyl-CoA acetyltransferase 1 (ACAT-1) was upregulated compared to naïve MDA-MB-231 cells and ATV treatment restored CDDP sensitivity, suggesting that aberrant ACAT-1 expression contributes to CDDP resistance in TNBC cells. Conclusions: These findings indicate that the elevated susceptibility of MDA-MB-231 cells to co-administration of CDDP and ATV, is associated with an increased reliance on CE availability. Our data from these cell culture-based studies supports the upregulation of cholesterol homeostasis as an adaptive response that contributes to aggressiveness and chemotherapy resistance.

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Linking Late Endosomal Cholesterol with Cancer Progression and Anticancer Drug Resistance

Cited by 11 publications

References 269 publications

ANXA6: a key molecular player in cancer progression and drug resistance

ANXA6: a key molecular player in cancer progression and drug resistance

Atorvastatin improves cisplatin sensitivity through modulation of cholesteryl ester homeostasis in breast cancer cells

Atorvastatin Improves Cisplatin Sensitivity Through Modulation of Cholesteryl Ester Homeostasis in Breast Cancer Cells

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