Evidence That Phosphatidylinositol 3-Kinase- and Mitogen-activated Protein Kinase Kinase-4/c-Jun NH2-terminal Kinase-dependent Pathways Cooperate to Maintain Lung Cancer Cell Survival

Abstract

Cancer cells in which theClass I phosphatidylinositol 3-kinase (PI3K) 1 consists of a family of heterodimeric complexes composed of a p110 catalytic subunit and a regulatory subunit that exists predominantly in a p85 form (1-3). The known gene family members for p85 (␣, ␤, and ␥) and p110 (␣, ␤, ␦, and ␥) are expressed in a tissuespecific fashion. p85␣ and -␤ can also exist in smaller forms (p50 and p55). PI3K phosphorylates the D3 position of PI on PI(4)P and PI(4,5)P to produce PI(3,4)P 2 and PI(3,4,5)P 3 . The 3Ј sites of PI(3,4)P 2 and PI(3,4,5)P 3 are dephosphorylated by the PTEN tumor suppressor, whereas the 5Ј site of PI(3,4,5)P 3 is dephosphorylated by SHIP to produce PI(3,4)P 2 (1). These mechanisms tightly regulate the levels of 3-phosphorylated PI in the cell. PI(3,4,5)P 3 and PI(3,4)P 2 recruit the pleckstrin homology domains of specific intracellular proteins to the plasma membrane, an essential event in the activation of PI3K-dependent kinases such as phosphoinositide-dependent kinase-1 and AKT, also known as protein kinase B. In addition, AKT phosphorylation at Thr 308 by phosphoinositide-dependent kinase-1 and Ser 473 by integrin-linked kinase (and possibly other kinases) constitutes an essential event in AKT activation (4, 5).The PI3K pathway clearly has a key role in cellular survival and transformation. AKT phosphorylates several pro-and antiapoptotic proteins, including the Bcl-2 family member BAD, caspase-9, cyclic AMP response element-binding protein,

Evidence of MKK4 pro-oncogenic activity in breast and pancreatic tumors

“…The biological activity of MKK4 in tumors has not been systematically examined. Our present in vitro and in vivo data using breast and pancreatic cancer cell lines are in agreement with the pro-oncogenic activities of MKK4 that may also be prevalent in other tumor types (Lee et al, 2003). …”

Simultaneous blockade of AP-1 and phosphatidylinositol 3-kinase pathway in non-small cell lung cancer cells

“…Using the H1299 NSCLC cells, Lee et al (2003Lee et al ( , 2005 reported that PI3K/Akt and MKK4/JNK pathways cooperated to promote cell proliferation by maintaining cell survival in vivo and in vitro, and simultaneous blockade of both pathways induced apoptosis . In this study, using the same cells, blocking these pathways with LY294002 and TAM67 enhanced cell proliferative arrest more than either agent alone, but neither agent alone nor their combination induced apoptosis.…”

“…In this study, using the same cells, blocking these pathways with LY294002 and TAM67 enhanced cell proliferative arrest more than either agent alone, but neither agent alone nor their combination induced apoptosis. Lee et al (2003Lee et al ( , 2005 used JNK inhibitor, SP600215 or a dominant-negative mutant of MKK4 to inhibit MKK4/JNK pathways, whereas we used the dominant-negative mutant of c-jun, TAM67. They speculated that the MKK4/JNK inhibitor induced apoptosis because JNK directly phosphorylates Bcl-2 in vitro and collaborates with Bcl-2 to mediate prolonged cell survival following various stress applications (Deng et al, 2001).…”

“…Clear evidence shows that the PI3K/Akt signalling pathway is involved in lung carcinogenesis (Brognard et al, 2001;Chun et al, 2003;Lee et al, 2003;Tsao et al, 2003;Massion et al, 2004). Akt is frequently activated in both premalignant human bronchial epithelial cells and NSCLC cells.…”

The ERBB3 receptor in cancer and cancer gene therapy

“…Accumulating evidence supports this role for the PI3K/AKT pathway. [389][390][391][392] The PI3K-AKT pathway was important in actions of tobacco carcinogens and in transformation-related characteristics of lung cells. 393,394 The JAK-STAT pathway may also be involved in NRG stimulation of proliferation of lung cells mediated by ERBB3.…”