Positive feedback in Cav‐1‐ROS signalling in PSCs mediates metabolic coupling between PSCs and tumour cells

Abstract

Caveolin‐1 (Cav‐1) is the principal structural component of caveolae, and its dysregulation occurs in cancer. However, the role of Cav‐1 in pancreatic cancer (PDAC) tumorigenesis and metabolism is largely unknown. In this study, we aimed to investigate the effect of pancreatic stellate cell (PSC) Cav‐1 on PDAC metabolism and aggression. We found that Cav‐1 is expressed at low levels in PDAC stroma and that the loss of stromal Cav‐1 is associated with poor survival. In PSCs, knockdown of Cav‐1 promoted the production of reactive oxygen species (ROS), while ROS production further reduced the expression of Cav‐1. Positive feedback occurs in Cav‐1‐ROS signalling in PSCs, which promotes PDAC growth and induces stroma‐tumour metabolic coupling in PDAC. In PSCs, positive feedback in Cav‐1‐ROS signalling induced a shift in energy metabolism to glycolysis, with up‐regulated expression of glycolytic enzymes (hexokinase 2 (HK‐2), 6‐phosphofructokinase (PFKP) and pyruvate kinase isozyme type M2 (PKM2)) and transporter (Glut1) expression and down‐regulated expression of oxidative phosphorylation (OXPHOS) enzymes (translocase of outer mitochondrial membrane 20 (TOMM20) and NAD(P)H dehydrogenase [quinone] 1 (NQO1)). These events resulted in high levels of glycolysis products such as lactate, which was secreted by up‐regulated monocarboxylate transporter 4 (MCT4) in PSCs. Simultaneously, PDAC cells took up these glycolysis products (lactate) through up‐regulated MCT1 to undergo OXPHOS, with down‐regulated expression of glycolytic enzymes (HK‐2, PFKP and PKM2) and up‐regulated expression of OXPHOS enzymes (TOMM20 and NQO1). Interrupting the metabolic coupling between the stroma and tumour cells may be an effective method for tumour therapy.

Caveolin-1 Alleviates Acetaminophen-Induced Fat Accumulation in Non-Alcoholic Fatty Liver Disease by Enhancing Hepatic Antioxidant Ability via Activating AMPK Pathway

“…CAV1, a regulator of redox homeostasis, can be modulated by reactive species in its expression, degradation, membrane trafficking, and posttranslational modifications, whereas the reactive species can be scavenged by CAV1-targeted treatments ( Martinez-Outschoorn et al, 2015 ; Shao et al, 2020 ). It has been found to play a protective role in NAFLD in our previous work ( Xue et al, 2020 ).…”

The Role of Stellate Cells in Pancreatic Ductal Adenocarcinoma: Targeting Perspectives

“…Furthermore, exosomes secreted by PSCs are abundant in cellular metabolites like amino acids and palmitate which fuel the TCA cycle in the nutrient-depleted TME, thereby accelerating the progression of PDAC ( 94 ). More recently, Shao et al found that the positive feedback occurred in Caveolin-1-reactive oxygen species (ROS) signaling in PSCs, leading to a conversion from energy metabolism to glycolysis in PSCs ( 95 ). Adjacent PCCs then took up the PSC-produced glycolysis products like lactate to perform oxidative phosphorylation ( 95 ).…”

“…More recently, Shao et al found that the positive feedback occurred in Caveolin-1-reactive oxygen species (ROS) signaling in PSCs, leading to a conversion from energy metabolism to glycolysis in PSCs ( 95 ). Adjacent PCCs then took up the PSC-produced glycolysis products like lactate to perform oxidative phosphorylation ( 95 ). As such, blocking the metabolic coupling between PSCs and PCCs may be a promising treatment for PDAC.…”

Role of reactive oxygen species in tumors based on the ‘seed and soil’ theory: A complex interaction (Review)

“…ROS can also reduce the expression of CAV1 and promote the transformation of myofibroblasts (87). In pancreatic, breast, lung and prostate cancer, it has been demonstrated that downregulation of CAV1 expression is associated with the overexpression of key metabolic enzymes, including pyruvate kinase isozymes M2 and LDH (180)(181)(182). In addition, the transport of lactic acid and ketone bodies, which are glycolytic products, can also be detected at the same time of CAV-1 downregulation (180)(181)(182).…”