Phospholipid Scramblases: Role in Cancer Progression and Anticancer Therapeutics

Abstract

Phospholipid scramblases (PLSCRs) that catalyze rapid mixing of plasma membrane lipids result in surface exposure of phosphatidyl serine (PS), a lipid normally residing to the inner plasma membrane leaflet. PS exposure provides a chemotactic eat-me signal for phagocytes resulting in non-inflammatory clearance of apoptotic cells by efferocytosis. However, metastatic tumor cells escape efferocytosis through alteration of tumor microenvironment and apoptotic signaling. Tumor cells exhibit altered membrane features, high constitutive PS exposure, low drug permeability and increased multidrug resistance through clonal evolution. PLSCRs are transcriptionally up-regulated in tumor cells leading to plasma membrane remodeling and aberrant PS exposure on cell surface. In addition, PLSCRs interact with multiple cellular components to modulate cancer progression and survival. While PLSCRs and PS exposed on tumor cells are novel drug targets, many exogenous molecules that catalyze lipid scrambling on tumor plasma membrane are potent anticancer therapeutic molecules. In this review, we provide a comprehensive analysis of scramblase mediated signaling events, membrane alteration specific to tumor development and possible therapeutic implications of scramblases and PS exposure.

A new immune signature for survival prediction and immune checkpoint molecules in non-small cell lung cancer

“…It was found that a high expression of FPR2 was associated with a lower OS in LUAD patients ( 8 ). ANO6 is a member of the TMEM16 family, which was initially discovered as Ca 2+ -activated Cl - ion channels ( 19 ). The TMEM16 family was found to be overexpressed in cancer cells associated with poor prognosis and cancer development.…”

Transcription regulation of human phospholipid scramblase 1 (hPLSCR1) by a Sry related high mobility group transcription factor, S-SOX5

“…Overexpression of hPLSCR1 in CHO-K1 cells activated caspase-3 and stimulated the PS biosynthesis (Yu et al 2003). On the other hand, the overexpression of hPLSCR1 showed an important role in various cancer types (Silverman et al 2002;Kuo et al 2011;Behuria et al 2022). hPLSCR1 helps in blood cell differentiation.…”

“…The Overexpression of PLSCR1 induces apoptosis and inhibits protective autophagy of NB4 leukemic cells and thus acts as a analytical marker for acute myelogenous leukemia (AML) (Behuria et al 2022). hPLSCR1 is a regulatory protein in Colorectal Carcinoma, Hepato-Pancreatic Carcinoma, Ovarian Cancer, and breast cancer (Silverman et al 2002;Kuo et al 2011;Behuria et al 2022). The overexpressed hPLSCR1 suppresses the tumorigenesis in HEY1B cell lines.…”

“…hPLSCR1 is a 37 kDa multifunctional protein known to regulate many vital functions in various cellular processes such as autoimmune diseases (Suzuki et al 2010), cell proliferation and differentiation (Zhou et al 2002), cell signaling (Nanjundan et al 2003;Amir-Moazami et al 2008), anti-viral defense (Dong et al 2004) and apoptosis (Frasch et al 2000;Yu et al 2003;Bailey et al 2005). It also plays an active role in cancer pathways like colorectal cancer, leukemia, hepato-pancreatic cancer, breast cancer, and ovarian cancer (Silverman et al 2002;Kuo et al 2011;Behuria et al 2022). hPLSCR1 acted as TF and up-regulated the expression of the IP3R1 gene by directly binding to its 5'-promoter region (Zhou et al 2005).…”

Dysregulation of cellular membrane homeostasis as a crucial modulator of cancer risk

“…Finally, alterations in the spatial organization of plasma membrane lipids have been associated with cancer risk. For example, the loss of PS asymmetric distribution between the exofacial and cytofacial membrane leaflets and increased PS exposure on the surface of malignant cells compared to healthy cells has been recently reported [606][607][608]. Notably, the efficacy of radiotherapy and chemotherapy-based anticancer treatments is dependent on the phenotype of PS exposure [609].…”