Dysregulated signaling through the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways is often the result of genetic alterations in critical components in these pathways or upstream activators. Unrestricted cellular proliferation and decreased sensitivity to apoptotic-inducing agents are typically associated with activation of these pro-survival pathways. This review discusses the functions these pathways have in normal and neoplastic tissue growth and how they contribute to resistance to apoptotic stimuli. Crosstalk and commonly identified mutations that occur within these pathways that contribute to abnormal activation and cancer growth will also be addressed. Finally the recently described roles of these pathways in cancer stem cells, cellular senescence and aging will be evaluated. Controlling the expression of these pathways could ameliorate human health.

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Integral components of these pathways, Ras, B-Raf, PI3K, and PTEN are also activated/inactivated by mutations. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of these pathways can contribute to chemotherapeutic drug resistance, proliferation of cancer initiating cells (CICs) and premature aging. This review will evaluate more recently described potential uses of MEK, PI3K, Akt and mTOR inhibitors in the proliferation of malignant cells, suppression of CICs, cellular senescence and prevention of aging. Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt/mTOR pathways play key roles in the regulation of normal and malignant cell growth. Inhibitors targeting these pathways have many potential uses from suppression of cancer, proliferative diseases as well as aging.

Mutations and chromosomal translocations occur in leukemic cells that result in elevated expression or constitutive activation of various growth factor receptors and downstream kinases. The Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways are often activated by mutations in upstream genes. The Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways are regulated by upstream Ras that is frequently mutated in human cancer. Recently, it has been observed that the FLT-3 and Jak kinases and the phosphatase and tensin homologue deleted on chromosome 10 ( PTEN) phosphatase are also frequently mutated or their expression is altered in certain hematopoietic neoplasms. Many of the events elicited by the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways have direct effects on survival pathways. Aberrant regulation of the survival pathways can contribute to uncontrolled cell growth and lead to leukemia. In this review, we describe the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT signaling cascades and summarize recent data regarding the regulation and mutation status of these pathways and their involvement in leukemia

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IntroductionAngiogenesis has a critical role in the pathophysiology and progression of multiple myeloma (MM) supporting the growth and survival of MM cells. [1][2][3][4][5] The angiogenic process in MM is sustained mainly by the overexpression of proangiogenic factors directly by MM cells including VEGF, 6 angiopoietin-1 (ANG-1), 7 osteopontin (OPN), . 9 Nevertheless, the molecular mechanisms underlying the regulation of angiogenesis in MM have not been completely elucidated.The new candidate tumor-suppressor gene inhibitor of growth family member 4 (ING4) has been recently implicated in solid tumors as a repressor of tumor growth and angiogenesis through the association with NF-B. ING4 is a nuclear factor expressed in all normal tissues and markedly reduced in glioblastoma cells and head and neck squamous cell carcinoma, with levels inversely correlated with tumor grade. 10,11 Inhibition of ING4 expression strongly promotes the growth of glioma cells in vivo, whereas its overexpression leads to growth inhibition through ING4's capability to interact with p65 subunit of NF-B. 10 Interestingly, it has been also shown that tumors lacking ING4 showed increased vascularization compared with ING4-expressing tumors. 12 Moreover ING4 down-regulated the angiogenic-related molecules including IL-8 and the hypoxia inducible factor-1␣ (HIF-1 ␣) activity in hypoxic condition through the involvement of HIF prolyl hydroxylase 2 (HPH-2) 10,13 In turn, the role of hypoxia has been recently highlighted in the promotion of angiogenesis. 14 The expression of ING4 by MM cells, as well as its potential role in MM-induced angiogenesis, has never been investigated. In this study, we evaluated the expression of ING4 in malignant MM cells and the potential relationship between ING4 and the production of proangiogenic molecules by MM cells in normoxic and hypoxic conditions, as well as its relationship with the "in vitro and in vivo" angiogenesis. Submitted February 15, 2007; accepted September 4, 2007. Prepublished online as Blood First Edition paper, September 11, 2007; DOI 10.1182 DOI 10. /blood-2007 The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on August 29, 2018. by guest www.bloodjournal.org From Patients, materials, and methods Cells and cell culture conditionsCell lines. Human myeloma cell lines (HMCLs) XG-6, XG-1, and JJN3 were obtained from Dr Bataille (Nantes, France). U266 was obtained from the American Type Culture Collection (Rockville, MD). OPM2 and RPMI-8226 were purchased from DSM (Braunschweig, Germany). ARP-1 and H929 were generously received from Dr Shaughnessy's laboratory (Little Rock, AR).Cell cultures. HMCLs were incubated in RPMI medium at 10% FCS (Invitrogen Life Technologies, Milan, Italy) and maintained with or without IL-6 (3 ng/mL; Endogen Woburn, MA). In a series of experiments, HMCLs were incubated with the HPH-2 in...