Involvement of the pathway phosphatidylinositol-3-kinase/AKT-1 in the establishment of the survival response to ionizing radiation

Cataldi, Amelia; Zauli, Giorgio; Pietro, Roberta Di; Castorina, Sergio; Rana, Rosa Alba

doi:10.1016/s0898-6568(01)00147-4

Cited by 39 publications

(20 citation statements)

References 40 publications

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“…Previous studies have shown that the PI3k inhibitors wortmannin or LY294002 can radiosensitize other types of cancer cells (20,21,23). A recent study demonstrated that expression of constitutively active PI3k in cells resulted in increased radioresistance (44).…”

Section: Discussionmentioning

confidence: 99%

Serine/Threonine Kinase AKT Is Frequently Activated in Human Bile Duct Cancer and Is Associated with Increased Radioresistance

et al. 2004

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The prognosis for patients with bile duct cancer (BDC) remains poor. Although BDC cells are essentially radioresistant, recent reports have suggested that radiation therapy, in addition to its palliative role in the management of BDC, may improve patient survival. A better understanding of the mechanisms that lead to cellular radioresistance may assist in the development of more effective BDC therapies based on radiotherapy in combination with radiosensitizing agents. The serine/threonine kinase AKT/protein kinase B, a downstream effector of phosphatidylinositol 3-kinase, is a well-characterized kinase that is known to play a critical role in antiapoptotic signaling pathways. In this investigation, we sought to clarify the role of AKT signaling in the radioresistance in BDC cells. First, to examine whether activated AKT is expressed in BDCs, tumor specimens were obtained from 19 consecutive BDC cases. Immunohistochemical staining using an anti-phosphorylated-AKT antibody showed that phosphorylated (activated) AKT was expressed in cancer cells but not in neighboring normal mucosa in 16 cases (84.2%). Next, to evaluate the role of AKT activation in the regulation of BDC cell radiosensitivity, clonogenic assays were performed using the phosphatidylinositol 3-kinase inhibitor LY294002 with and without irradiation. LY294002 inhibited AKT activation in BDC cells and, on irradiation, decreased clonogenic survival in a radiation dose-dependent manner. Only a small decrease in cell viability was observed in cells exposed to LY294002. Expression of constitutively active AKT in BDC cells resulted in decreased radiosensitivity, whereas a dominant-negative AKT increased radiosensitivity. Furthermore, constitutively active AKT also inhibited radiation-induced apoptosis. Collectively, these results indicate that activated AKT in BDC cells is associated with radioresistance and suggest that pharmacological or genetic modulation of AKT activity may have important therapeutic implications in BDC patients treated with radiation.

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Section: Discussionmentioning

confidence: 99%

Serine/Threonine Kinase AKT Is Frequently Activated in Human Bile Duct Cancer and Is Associated with Increased Radioresistance

et al. 2004

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“…Testa and Bellacosa (2001) have pointed out that as a general mechanism phosphorylation events downstream of AKT frequently affect nuclear translocation of factors involved either in the regulation of cell cycle progression or of apoptosis. For example, AKT activates IKK resulting in NF-kB transcription of antiapoptotic genes (reviewed in Testa and Bellacosa, 2001;Thakkar et al, 2001;Cataldi et al, 2001;Chan et al, 2002;Edwards et al, 2002;Li and Zhu, 2002;Nicholson and Anderson, 2002). In this regard, however, both Tofilon (Russell et al, 2002) and Cox (Grana et al, 2002) have produced data suggesting that NF-kB is not involved in the altered radiosensitivity seen with RAS.…”

Section: Recent Studies On Ras and Radiation Sensitivitymentioning

confidence: 99%

The RAS signal transduction pathway and its role in radiation sensitivity

et al. 2003

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RAS has been shown to increase radiation resistance. Upstream and downstream pathways from RAS could thus be targets for manipulation of radiosensitivity. EGFR expression and AKT phosphorylation are also associated with the response to radiation. A retrospective study evaluating EGFR and AKT in patients treated with multimodality therapy found a significant association between P-AKT and treatment failure. Moreover, these data are strengthened by in vitro studies showing that inhibition of EGFR, RAS, PI3K, and AKT radiosensitized cancer cell lines. We have previously shown that PI3K is a mediator of RAS-induced radiation resistance. We now suggest that EGFR, which is upstream of PI3K, may also mediate resistance through a common pathway. In addition to EGFR and RAS, PTEN can also regulate the PI3K pathway. Identifying a common signal for EGFR, RAS, or PTEN that results in radiation resistance may uncover targets for developing molecular-based radiosensitization protocols for tumors resistant to radiation and thus improve local control.

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“…[14][15][16] On the other hand, limited information is available regarding the role played by the PI3K /Akt axis in determining resistance to these treatments in cells of hematopoietic lineage. [17][18][19] In these studies, inhibition of the PI3K /Akt pathway was obtained by means of two pharmacological inhibitors of the PI3K catalytic subunit, wortmannin and Ly294002. However, these two inhibitors have some limitations.…”

Section: Introductionmentioning

confidence: 99%

A new selective AKT pharmacological inhibitor reduces resistance to chemotherapeutic drugs, TRAIL, all-trans-retinoic acid, and ionizing radiation of human leukemia cells

et al. 2003

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Involvement of the pathway phosphatidylinositol-3-kinase/AKT-1 in the establishment of the survival response to ionizing radiation

Cited by 39 publications

References 40 publications

Serine/Threonine Kinase AKT Is Frequently Activated in Human Bile Duct Cancer and Is Associated with Increased Radioresistance

Serine/Threonine Kinase AKT Is Frequently Activated in Human Bile Duct Cancer and Is Associated with Increased Radioresistance

The RAS signal transduction pathway and its role in radiation sensitivity

A new selective AKT pharmacological inhibitor reduces resistance to chemotherapeutic drugs, TRAIL, all-trans-retinoic acid, and ionizing radiation of human leukemia cells

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