The phosphatidylinositol 3-kinase/Akt and c-Jun N-terminal kinase signaling in cancer: Alliance or contradiction? (Review)

Zhao, Hua; Wang, Jing; To, Suet

doi:10.3892/ijo.2015.3052

Cited by 106 publications

(70 citation statements)

References 92 publications

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“…Studies have shown that specific anti-sense oligonucleotides against JNK lead to decreased cell growth by promoting apoptosis in gastric, lung and prostate cancer cells (104, 105). On the other hand, the observed decrease in proliferation of TRPM2 KD cells could be due to a decrease in p-AKT (106,107); crosstalk between JNK and AKT signalling pathways has been established and shown to inhibit apoptosis as a means of promoting cancer cell survival (108). Altogether, our study provides new evidence that TRPM2 triggers both, the AKT and JNK signalling pathways to promote gastric cancer cell survival.…”

Section: Discussionsupporting

confidence: 49%

TRPM2 channel–mediated regulation of autophagy maintains mitochondrial function and promotes gastric cancer cell survival via the JNK-signaling pathway

Almasi¹,

Kennedy

Elaghil

et al. 2018

Journal of Biological Chemistry

107

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A lack of effective treatment is one of the main factors contributing to gastric cancerrelated death. Discovering effective targets and understanding their underlying anticancer mechanism is key to achieving the best response to treatment and to limiting side effects. Although recent studies have shown that the cation channel transient receptor potential melastatin-2 (TRPM2) is crucial for cancer cell survival, the exact mechanism remains unclear, limiting its therapeutic potential. Here, using molecular and functional assays, we investigated the role of TRPM2 in survival of gastric cancer cells. Our results indicated that TRPM2 knockdown in AGS and MKN-45 cells decreases cell proliferation and enhances apoptosis. We also observed that the TRPM2 knockdown impairs mitochondrial metabolism, indicated by a decrease in basal and maximal mitochondrial oxygen consumption rates (OCRs) and ATP production. These mitochondrial defects coincided with a decrease in autophagy and mitophagy, indicated by reduced levels of autophagyand mitophagy-associated proteins (i.e. ATGs, LC3A/B II, and BNIP3). Moreover, we found that TRPM2 modulates autophagy through a JNK-dependent and mechanistic target of rapamycin (mTOR)-independent pathway. We conclude that in the absence of TRPM2, down-regulation of the JNK signaling pathway impairs autophagy, ultimately causing the accumulation of damaged mitochondria and death of gastric cancer cells. Of note, by inhibiting cell proliferation and promoting apoptosis, the TRPM2 down-regulation enhanced the efficacy of paclitaxel and doxorubicin in gastric cancer cells. Collectively, we provide compelling evidence that TRPM2 inhibition may benefit therapeutic approaches for managing gastric cancer.Gastric cancer is the fifth most common type of cancer worldwide, affecting millions each year (1-4). The five-year survival rate is estimated at approximately 30% (5) making it one of the deadliest malignancies in the world and the second leading cause of cancer-related mortality in Eastern Asia (6, 7). Currently, surgery is the most effective available therapy against gastric cancer; however, its efficacy is limited to the early-stage gastric cancer patients (8, 9). For patients with late-stage tumors, surgery is not an option and despite systemic chemotherapy, the disease is deemed incurable (10)(11)(12). Considering the poor efficacy of current anticancer agents, the increasing resistance to chemotherapy drugs and the lack of treatment options for late stage patients, the development of novel and effective therapeutic approaches is of critical importance.Over the last decade, Transient Receptor Potential (TRP) channels have gained considerable attention in the field of cancer-targeted therapy (13-16). TRP channels are often altered in cancer cells and disruption in their normal function can affect various signalling pathways, ultimately leading to cancer progression and growth (17, 18). The TRP family is divided into seven subfamilies consisting of a total of 28 members. Some of members inclu...

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Section: Discussionsupporting

confidence: 49%

TRPM2 channel–mediated regulation of autophagy maintains mitochondrial function and promotes gastric cancer cell survival via the JNK-signaling pathway

Almasi¹,

Kennedy

Elaghil

et al. 2018

Journal of Biological Chemistry

107

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“…Stress activated protein kinases, such as JNK and p38, are activated by various stress stimuli. 33 Bioactive compounds are known to induce apoptosis by activating JNK and p38. Consistent with these results, we observed that JNK and p38 activation was involved in ω-HUA-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

ω‐hydroxyundec‐9‐enoic acid induces apoptosis by ROS mediated JNK and p38 phosphorylation in breast cancer cell lines

Ahn¹,

Chung

Park³

et al. 2017

J of Cellular Biochemistry

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ω-Hydroxyundec-9-enoic acid (ω-HUA), a plant secondary metabolite, exhibits anti-fungal activity. However, its effect on breast cancer cells is unknown. Here, we investigated the anti-breast cancer activity of ω-HUA and its underlying mechanism. Treatment of human breast cancer cell lines, MDA-MB-231 and MDA-MB-435, with ω-HUA induced apoptotic cell death with increased cleaved caspase-3 and poly (ADP-ribose) polymerase (PARP) levels, and p38 and JNK phosphorylation. Inhibition of these mitogen-activated protein kinase (MAPK) pathways using specific inhibitors or siRNA, for p38 and JNK, respectively, blocked the ω-HUA-induced apoptosis in a dose-dependent manner. Moreover, pretreatment of the cells with antioxidant N-acetyl cysteine (NAC) inhibited ω-HUA-induced increased reactive oxygen species (ROS) levels, cleaved caspase-3 and cleaved PARP, and phosphorylated JNK, phosphorylated p38, and increased cell viability and colony-forming ability. MDA-MB-231 xenograft model showed that the ω-HUA-treated group exhibited greater tumor regression and significantly reduced tumor weight compared to that exhibited by the vehicle-administered group. Collectively, ω-HUA-induced intracellular ROS generation induced breast cancer cell apoptosis through JNK and p38 signaling pathway activation, resulting in tumor regression. The results suggested that ω-HUA is an effective supplement for inhibiting human breast cancer growth. K E Y W O R D Santi-cancer effect, apoptosis, JNK pathway, p38 pathway, ROS, ω-Hydroxyundec-9-enoic acid | INTRODUCTIONBreast cancer is the most frequently diagnosed cancer and the leading cause of cancer-related deaths among women. 1The known risk factors include not only older age and family history, but also obesity, excessive drinking, and ionizing radiation; it is generally more aggressive than after menopause.1-3 Compared to the 5-year survival rate of >80% in England and the United States, that in the other countries remains low. 4 Breast cancer can be treated by surgery, radiation therapy, chemotherapy, hormonal therapy, targeted therapy, and drugs, such as tamoxifen and raloxifene. 5-9The intake of dietary fats has long been associated with the prevention and treatment of chronic diseases, such as cancer. Marine resource-derived polyunsaturated fatty acids 998 |

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“…Combination of NVP-BEZ235 and MEK1/2 inhibitors UO126 or SL327 displays synergistic inhibitory effect on self-renewal and tumorigenic capacities of GBM stem-like cells (GSLCs), and prolongs the survival of mice with GSLC xenograft [96]. In addition, PI3K/Akt and MKK4/JNK pathways also co-operate to regulate cancer cell survival, migration and invasion [117]. Our previous study showed that concurrent inhibition of PI3Kβ and JNK synergistically suppresses GBM cell proliferation and migration, and tumor growth in U-87 MG xenograft mice [19].…”

Section: Introductionmentioning

confidence: 99%

Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development

et al. 2017

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Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary tumor in the central nervous system. One of the most widely used chemotherapeutic drugs for GBM is temozolomide, which is a DNA-alkylating agent and its efficacy is dependent on MGMT methylation status. Little progress in improving the prognosis of GBM patients has been made in the past ten years, urging the development of more effective molecular targeted therapies. Hyper-activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is frequently found in a variety of cancers including GBM, and it plays a central role in the regulation of tumor cell survival, growth, motility, angiogenesis and metabolism. Numerous PI3K inhibitors including pan-PI3K, isoform-selective and dual PI3K/mammalian target of rapamycin (mTOR) inhibitors have exhibited favorable preclinical results and entered clinical trials in a range of hematologic malignancies and solid tumors. Furthermore, combination of inhibitors targeting PI3K and other related pathways may exert synergism on suppressing tumor growth and improving patients’ prognosis. Currently, only a handful of PI3K inhibitors are in phase I/II clinical trials for GBM treatment. In this review, we focus on the importance of PI3K/Akt pathway in GBM, and summarize the current development of PI3K inhibitors alone or in combination with other inhibitors for GBM treatment from preclinical to clinical studies.

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The phosphatidylinositol 3-kinase/Akt and c-Jun N-terminal kinase signaling in cancer: Alliance or contradiction? (Review)

Cited by 106 publications

References 92 publications

TRPM2 channel–mediated regulation of autophagy maintains mitochondrial function and promotes gastric cancer cell survival via the JNK-signaling pathway

TRPM2 channel–mediated regulation of autophagy maintains mitochondrial function and promotes gastric cancer cell survival via the JNK-signaling pathway

ω‐hydroxyundec‐9‐enoic acid induces apoptosis by ROS mediated JNK and p38 phosphorylation in breast cancer cell lines

Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development

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