Grape seed extract targets mitochondrial electron transport chain complex III and induces oxidative and metabolic stress leading to cytoprotective autophagy and apoptotic death in human head and neck cancer cells

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a major killer worldwide and innovative measures are urgently warranted to lower the morbidity and mortality caused by this malignancy. Aberrant redox and metabolic status in HNSCC cells offer a unique opportunity to specifically target cancer cells. Therefore, we investigated the efficacy of grape seed extract (GSE) to target the redox and bioenergetic alterations in HNSCC cells. GSE treatment decreased the mitochondrial electron transport chain complex III activity, increased the mitochondrial superoxide levels and depleted the levels of cellular antioxidant (glutathione), thus resulting in the loss of mitochondrial membrane potential in human HNSCC Detroit 562 and FaDu cells. Polyethylene glycol-SOD addition reversed the GSE-mediated apoptosis without restoring complex III activity. Along with redox changes, GSE inhibited the extracellular acidification rate (representing glycolysis) and oxygen consumption rate (indicating oxidative phosphorylation) leading to metabolic stress in HNSCC cells. Molecular studies revealed that GSE activated AMP-activated protein kinase (AMPK), and suppressed Akt/mTOR/4E-BP1/S6K signaling in both Detroit 562 and FaDu cells. Interestingly, GSE increased the autophagic load specifically in FaDu cells, and autophagy inhibition significantly augmented the apoptosis in these cells. Consistent with in vitro results, in vivo analyses also showed that GSE feeding in nude mice activated AMPK and induced-autophagy in FaDu xenograft tumor tissues. Overall, these findings are innovative as we for the first time showed that GSE targets ETC complex III and induces oxidative and metabolic stress, thereby, causing autophagy and apoptotic death in HNSCC cells.

Procyanidin B2 3,3″‐di‐O‐gallate induces oxidative stress‐mediated cell death in prostate cancer cells via inhibiting MAP kinase phosphatase activity and activating ERK1/2 and AMPK

“…Earlier reports have shown that GSE causes cell death in human head and neck and bladder carcinoma cells by oxidative stress induction, and since B2G2 is the major active constituent of GSE, we next measured whether B2G2 also induces ROS generation in human PCa LNCaP and 22Rv1 cells using DCFDA as a probe compound. Results showed a robust ROS generation by B2G2 treatment in both LNCaP and 22Rv1 cells (Figures D and E).…”

“…Along with the failure of several antioxidants, there is plethora of the literature suggesting that elevated intracellular ROS level provides cancer cells an aggressive phenotype; however, ROS levels above a particular threshold could be deleterious to cancer cells . Therefore, recent research efforts have also focused onto increase ROS production in cancer cells via compounds displaying pro‐oxidant properties . Importantly, compared to normal prostate epithelial cells, PCa cells generate higher amounts of ROS making them more prone to ROS‐induced damages; enhanced ROS levels trigger pro‐apoptotic signaling pathways as the anti‐oxidant defense mechanisms are already compromised in these cancer cells .…”

“…Importantly, compared to normal prostate epithelial cells, PCa cells generate higher amounts of ROS making them more prone to ROS‐induced damages; enhanced ROS levels trigger pro‐apoptotic signaling pathways as the anti‐oxidant defense mechanisms are already compromised in these cancer cells . In this regard, several dietary agents including grape seed extract (GSE) have been identified to cause apoptotic cell death in cancer cells by inducing oxidative stress . GSE is a naturally occurring dietary agent with proven potential against various malignancies, including PCa .…”

Mitochondrial dysfunction and lipid peroxidation in rat frontal cortex by chronic NMDA administration can be partially prevented by lithium treatment

“…Complex III, also known as cytochrome c reductase, acts similarly to complex I by extracting electrons from ubiquinol to reduce cytochrome c (Denis, 1986; Pramanik et al, 2011). The ability of complexes I and III to act as electron transporters suggests that reduced levels of these complexes may increase generation of oxidative stress from the mitochondria by allowing electrons to leak from the system to react with molecular oxygen, generating ROS (Janssen et al, 2006; Li et al, 2003; Shrotriya et al, 2015). Oxidative damage can disrupt enzymes and transporters, change expression of certain genes or activate inflammation through redox sensors and activate apoptosis (Fariss et al, 2005; Kim et al, 2014; Naoi et al, 2005; Ray et al, 2012; Zhou et al, 2011).…”

A novel PI3K axis selective molecule exhibits potent tumor inhibition in colorectal carcinogenesis

“…The PI3K/Akt pathway regulates the autophagy via its effector proteins and signalling molecules like mTORC, Bcl‐2, Beclin‐1 and ROS . The kinase mTOR is a critical regulator of autophagy induction, with activated mTOR (Akt and MAPK signaling) suppressing autophagy .…”