The role of Popeye domain‐containing protein 1 (POPDC1) in the progression of the malignant phenotype

Abstract

The Popeye domain-containing protein 1 (POPDC1), a tight junction-associated transmembrane protein with a unique binding site for cAMP, has been shown to act as a tumour suppressor in cancer cells. Through interaction with many downstream effectors and signalling pathways, POPDC1 promotes cell adhesion and inhibits uncontrolled cell proliferation, epithelial-to-mesenchymal transition and metastasis.However, POPDC1 expression is down-regulated in many types of cancer, thereby reducing its tumour-suppressive actions. This review discusses the role of POPDC1 in the progression of the malignant phenotype and highlights the broad range of benefits POPDC1 stabilisation may achieve therapeutically. Cancer stem cells (CSCs) are a key hallmark of malignancies and commonly promote treatment resistance. This article provides a comprehensive overview of CSC signalling mechanisms, many of which have been shown to be regulated by POPDC1 in other cell types, thus suggesting an additional therapeutic benefit for POPDC1-stabilising anti-cancer drugs.

Themed issue: ‘New avenues in cancer prevention and treatment’

“…Tucker and Zorn (2022) further discuss evidence of diverse functions among novel targets in cancer where members of the same family of Popeye domain‐containing (POPDC) proteins may play opposing roles depending on the cancer type (Tucker & Zorn, 2022). POPDC1 is the most studied isoform and seems to have the most consistent tumour‐suppressive role in the majority of cancers.…”

“…This transmembrane protein contains a binding site for cAMP and indeed cAMP binding to the Popeye domain of POPDC1 increases POPDC1 expression, stabilization and activation (Amunjela & Tucker, 2017). Tucker and Zorn (2022) describe mechanisms of POPDC1‐mediated promotion of cell adhesion and inhibition of cell proliferation and metastasis. For instance, POPDC1 interacts with tight junction‐associated proteins to maintain cell adhesion, whereas the c‐Myc transcription factor and WNT signalling pathway is linked to POPDC1‐mediated inhibition of uncontrolled cell growth.…”

“…Indeed, the loss of POPDC1 expression has been shown to disrupt cell adhesion which is the first stage of the EMT pathway contributing to the cellular spread. Tucker and Zorn (2022) also emphasize that because the Rho family of GTPases are a challenging drug target, stabilizing POPDC1 could constitute an effective alternative approach in therapies aimed at inhibition of RhoGTPases. In addition, since POPDC1 targets, such as WNT signalling, c‐Myc and RhoGTPases, are key for cancer stem cell (CSC) functioning, the connection between POPDC1 and a weakening of the CSC network becomes apparent and is worth further investigation (Tucker & Zorn, 2022).…”

“…Tucker and Zorn (2022) also emphasize that because the Rho family of GTPases are a challenging drug target, stabilizing POPDC1 could constitute an effective alternative approach in therapies aimed at inhibition of RhoGTPases. In addition, since POPDC1 targets, such as WNT signalling, c‐Myc and RhoGTPases, are key for cancer stem cell (CSC) functioning, the connection between POPDC1 and a weakening of the CSC network becomes apparent and is worth further investigation (Tucker & Zorn, 2022). Of further interest, Tucker and Zorn (2022) mention recent discoveries implying that cancer stem cells could arise during EMT, contributing to resistance to both traditional chemotherapy and immunotherapy.…”

“…In addition, since POPDC1 targets, such as WNT signalling, c‐Myc and RhoGTPases, are key for cancer stem cell (CSC) functioning, the connection between POPDC1 and a weakening of the CSC network becomes apparent and is worth further investigation (Tucker & Zorn, 2022). Of further interest, Tucker and Zorn (2022) mention recent discoveries implying that cancer stem cells could arise during EMT, contributing to resistance to both traditional chemotherapy and immunotherapy. Thus, inhibiting EMT through stabilizing POPDC1 could consequently decrease cancer stemness and improve patient outcomes (Tucker & Zorn, 2022).…”