Abstract
The cytolinker and scaffolding protein, plectin, has emerged as a potent driver of malignant hallmarks in many human cancers due to its involvement in various cellular activities contributing to tumorigenesis, including cancer cell proliferation, adhesion, migration, invasion, and signal transduction. Evidence shows that beyond plectin’s diverse protein interactome, its cancer-specific mislocalization to the cell surface enables its function as a potent oncoprotein. As such, therapeutic targeting of plectin, its protein interactors, and, in particular, cancer-specific plectin (CSP) presents an attractive opportunity to impede carcinogenesis directly. Here, we report on plectin’s differential gene and protein expression in cancer, explore its mutational profile, and discuss the current understanding of plectin’s and CSP’s biological function in cancer. Moreover, we review the landscape of plectin as a prognostic marker, diagnostic biomarker, and target for imaging and therapeutic modalities. We highlight how, beyond their respective biological importance, plectin’s common overexpression in cancer and CSP’s cancer-specific bioavailability underscore their potential as high-value druggable targets. We discuss how recent evidence of the potent anti-cancer effects of CSP therapeutic targeting opens the door for cell-surface mislocalized proteins as novel therapeutic targets.
Highlights
First identified over four decades ago, plectin is a 500 kDa protein commonly expressed in mammalian tissues and cell types [1]
Plectin is a scaffolding protein known to bind to the receptor for activated C kinase 1 (RACK1), modulating protein kinase C (PKC) signaling pathways, and it has been shown to interact with phosphatidylinositol-4,5-biphosphate (PIP2) [7], integrin α6β4 [8], and calmodulin [9], among others
Contrary to the influx of targets identified by genetic and sequencing strategies, plectin is a notable target identified by an alternative drug discovery approach that emphasizes cell-surface localization
Summary
First identified over four decades ago, plectin is a 500 kDa protein commonly expressed in mammalian tissues and cell types [1]. Plectin’s cancer-specific cell surface mislocalization has revealed plectin expression as a biomarker or prognostic indicator in several cancers, including pancreatic, ovarian, lung, prostate, and head and neck cancer [10,11,13,14,15,16,17]. To this end, multiple groups have successfully leveraged cancer-specific plectin’s (CSP) abundant and bioavailable expression to guide imaging agents and drug delivery systems [13,15,18,19,20,21,22,23,24]. We review the current understanding of plectin’s critical role in cancer biology, its diagnostic capabilities, and its therapeutic potential, all of which underscore its far-reaching biologic significance and clinical utility
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