PI3K/Akt/mTOR pathway inhibitors enhance radiosensitivity in radioresistant prostate cancer cells through inducing apoptosis, reducing autophagy, suppressing NHEJ and HR repair pathways

Chang, Lei; Graham, Peter; Hao, Jingli; Ni, Jie; Bucci, Joseph; Cozzi, Paul; Kearsley, John H.; Li, Y.

doi:10.1038/cddis.2014.415

Cited by 263 publications

(207 citation statements)

References 30 publications

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“…The PI3K/Akt/mTOR signaling pathway promotes cellular growth, migration, protein synthesis, survival and metabolism in response to growth factors and nutrient availability (8). PI3K activates Akt, which leads to the phosphorylation of mTOR via a number of regulators (17). In the present study, Licochalcone A suppressed the PI3K/Akt/mTOR signaling pathway in MCF-7 cells.…”

Section: Discussionsupporting

confidence: 48%

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Licochalcone A inhibits PI3K/Akt/mTOR signaling pathway activation and promotes autophagy in breast cancer cells

et al. 2017

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Abstract. Previous studies have demonstrated that LicochalconeA possesses anti-inflammatory, anticancer, anti-bacterial, anti-malarial and anti-parasitic activities. In the present study the potential anticancer effects of Licochalcone A on MCF-7 cells were investigated. Licochalcone A significantly decreased cell viability and promoted autophagy and apoptosis, as demonstrated by an MTT assay, acridine orange staining and Annexin V-fluorescein isothiocyanate staining, respectively. Western blot analyses demonstrated that Licochalcone A treatment activated the LC3-II signaling pathway while suppressing the phosphoinositide 3-kinase (PI3K)/RAC-α serine-threonine-protein kinase (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. In addition, Licochalcone A significantly increased caspase-3 activity and significantly decreased B-cell lymphoma-2 expression. The results from the present study indicate that Licochalcone A inhibits PI3K/Akt/mTOR activation, and promotes autophagy and apoptosis in MCF-7 cells.

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Section: Discussionsupporting

confidence: 48%

“…Autophagy promotes the survival of cells and maintains homeostasis by degrading damaged organelles and proteins (17). The PI3K/Akt/mTOR signaling pathway promotes cellular growth, migration, protein synthesis, survival and metabolism in response to growth factors and nutrient availability (8).…”

Section: Discussionmentioning

confidence: 99%

Licochalcone A inhibits PI3K/Akt/mTOR signaling pathway activation and promotes autophagy in breast cancer cells

et al. 2017

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“…We found that knockdown of HMBOX1 decreased the expression of ATM, ATR and BRCA1 with or without ionizing radiation exposure, as well as phospho-ATM and phospho-ATR. Previous studies have verified that ATM, and ATR expression levels are closely related to radiosensitivity in cancer cells (20)(21)(22)(23)(24), and inhibition of radiation-induced DNA damage repair is believed to lead to radiosensitization (25). Our data indicate that knockdown of HMBOX1 resulted in lower expression of ATM, ATR and BRCA1 in the HR pathway.…”

Section: Discussionsupporting

confidence: 72%

Knockdown of homeobox containing 1 increases the radiosensitivity of cervical cancer cells through telomere shortening

et al. 2017

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Abstract. Homeobox containing 1 (HMBOX1) modulates telomere length in various types of tumor cells by binding to double-stranded telomeric DNA. There is a negative correlation between telomere length and radiosensitivity in tumor cells. In the present study, we aimed to investigate the relationship among HMBOX1, telomere and radiosensitivity in cervical cancer cells. Lentivirus-based shRNAs were used to establish stable transfected cell lines in which protein and mRNA levels of HMBOX1 were notably decreased. Knockdown of HMBOX1 increased the radiosensitivity of HeLa and C33A cells. TERT protein was also decreased while HMBOX1 was downregulated. Knockdown of HMBOX1 shortened telomere length in the HeLa cells, while TERT overexpression rescued telomere shortening in the HeLa-HMBOX1 cells. Knockdown of HMBOX1 increased the apoptosis rate, decreased radiationinduced DNA damage foci, and inhibited the expression of ATM, ATR, p-ATM, p-ATR and BRCA1 in the homologous recombination repair pathway. Our data suggest a possible role of HMBOX1 in regulating radiosensitivity in cervical cancer cells. Moreover, HMBOX1 may be a potential factor in the radiotherapy of cervical cancer. IntroductionCervical cancer is the most common malignant tumor of the female reproductive system. It is the second most commonly diagnosed cancer and the third leading cause of cancerrelated death among females in developing countries (1). Radiotherapy is the major treatment for cervical cancer. For patients with early-stage disease, radiotherapy and surgery alone have equal effects. In recent years, chemoradiotherapy has gradually become a new treatment pattern for patients with locally advanced disease. It has been demonstrated that radiotherapy plays a crucial role in the treatment of cervical cancer. However, patients who suffer pelvic recurrence account for ~70% of the cases of radiotherapy failure (2). Thus, the identification of new factors that influence radiosensitivity has important significance in cervical cancer treatment.Homeobox containing 1 (HMBOX1), a new member of the homeobox genes, was identified and isolated from the human pancreatic cDNA library. HMBOX1 was described as a transcription repressor (3). In the ALT (alternative lengthening of telomeres) cell line WI38-VA13 and telomerase-positive HeLa cells, HMBOX1 was identified as a double-stranded telomeric DNA binding protein (4) and acted as a positive regulator of telomere length (5). In U2OS (ALT cells), HMBOX1 was found to modulate telomere maintenance without influencing telomere length (6). However, the further function of HMBOX1 is not fully clear.Telomeres, nucleoprotein complexes at the end of eukaryotic chromosomes, are composed of 5'-TTAGGG-3' repeats and are maintained by telomerase. Telomeres contain protein complexes and shelterin, and play a crucial role in protecting chromosome ends from DNA damage. Moreover, telomere length may serve as a target in predicting the individual radiosensitivity of patients with cancers (7-11).However, to date, the relationship bet...

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“…In addition, there are many molecules involved in the control and regulation of sensitivity to irradiation therapy in PCa, and elucidation of the molecular mechanisms underlying the enhanced radioresponse of SQAP is critical. [22][23][24][25][26] SQAP has several characteristics. First, although the agent alone has no substantial effect on tumor growth at low concentrations, it induces radiosensitizing effects.…”

Section: Discussionmentioning

confidence: 99%

Sulfoquinovosylacylpropanediol is a novel potent radiosensitizer in prostate cancer

et al. 2015

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Abbreviations & Acronyms α-SQMG = α-sulfoquinovosylmonoacylglycerol DAPI = 4´6´-diamindino-2-phenylindole dihydrochloride PBS = phosphate-buffered saline PCa = prostate cancer SMA = smooth muscle actin SQAP = sulfoquinovosylacylpropanediol XRT = X-ray irradiation Objectives: To examine the effects of combined treatment with sulfoquinovosylacylpropanediol and X-ray irradiation on the remodeling of the prostate cancer microenvironment, including angiogenic and hypoxic characteristics. Methods: Human prostate cancer cells (DU145 and PC3) were implanted subcutaneously into the right hind legs of athymic nude mice. After the tumor volume reached 100-300 mm 3 , 2 mg/kg/day sulfoquinovosylacylpropanediol was given intravenously from day 0 to day 4, and cells were exposed to 4 Gy X-ray irradiation on days 0 and 3 (for a total of 8 Gy). Tumors were fixed and stained for pathological analyses and immunohistochemical evaluations. To analyze vascular normalization, 60 mg/kg pimonidazole dissolved in saline was injected intraperitoneally. Results: Combined treatment with sulfoquinovosylacylpropanediol plus X-ray irradiation enhanced growth inhibition in DU145 xenografts. The tumor vessel density in DU145 cells significantly decreased after the combined treatment. Staining for smooth muscle actin in vessels was significantly increased. Pimonidazole staining, showing hypoxic lesions, was negative from 72 h, but positive at 6 and 24 h after the first combined treatment. In contrast, no enhancement of the microenvironment in PC3 xenografts was observed with sulfoquinovosylacylpropanediol plus X-ray irradiation. Conclusion: Sulfoquinovosylacylpropanediol could be a novel potent radiosensitizing agent targeting angiogenesis in prostate cancer.

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PI3K/Akt/mTOR pathway inhibitors enhance radiosensitivity in radioresistant prostate cancer cells through inducing apoptosis, reducing autophagy, suppressing NHEJ and HR repair pathways

Cited by 263 publications

References 30 publications

Licochalcone A inhibits PI3K/Akt/mTOR signaling pathway activation and promotes autophagy in breast cancer cells

Licochalcone A inhibits PI3K/Akt/mTOR signaling pathway activation and promotes autophagy in breast cancer cells

Knockdown of homeobox containing 1 increases the radiosensitivity of cervical cancer cells through telomere shortening

Sulfoquinovosylacylpropanediol is a novel potent radiosensitizer in prostate cancer

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