Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2021

01-12-2021 | Human Papillomavirus | Research article

Raptor and rictor expression in patients with human papillomavirus-related oropharyngeal squamous cell carcinoma

Authors: Shunsuke Kondo, Hitoshi Hirakawa, Taro Ikegami, Takayuki Uehara, Shinya Agena, Jin Uezato, Hidetoshi Kinjyo, Noritomo Kise, Yukashi Yamashita, Katsunori Tanaka, Narumi Hasegawa, Asanori Kiyuna, Hiroyuki Maeda, Mikio Suzuki, Akira Gahana

Published in: BMC Cancer | Issue 1/2021

Login to get access

Abstract

Background

Despite reports of a link between human papillomavirus (HPV) infection and mechanistic target of rapamycin (mTOR) signaling activation, the role of the mTOR pathway, especially raptor and rictor, in HPV-related head and neck cancer is still unclear. The aim of the present study was to elucidate the role of the mTOR pathway in HPV-related oropharyngeal squamous cell carcinoma (OPSCC).

Methods

The present study involved two strategies. The first was to investigate the activity of mTOR and mTOR-related complexes in high-risk HPV-positive (UM-SCC47 and CaSki) and HPV-negative (SCC-4 and SAS) cancer cell lines. The second was to elucidate mTOR complex expression in 80 oropharyngeal cancer tissues and to examine the relationship between mTOR complex expression and survival in patients with OPSCC.

Results

The UM-SCC47 and CaSki cell lines showed high gene and protein expression of raptor. They also exhibited G1/S and G2/M phase cell cycle arrest following 24 h incubation with 6 μM temsirolimus, a rapamycin analog, and temsirolimus administration inhibited their growth. HPV-related OPSCC samples showed high gene and protein expression of raptor and rictor compared with HPV-unrelated OPSCC. In addition, HPV-related OPSCC patients with high raptor and rictor expression tended to have a worse prognosis than those with low or medium expression.

Conclusions

These results suggest that raptor and rictor have important roles in HPV-related OPSCC and that temsirolimus is a potential therapeutic agent for patients with HPV-related OPSCC. This is the first report to reveal the overexpression of raptor and rictor in HPV-related OPSCC.
Appendix
Available only for authorised users
Literature
1.
2.
Kim LC, Cook RS, Chen J. mTORC1 and mTORC2 in cancer and the tumor microenvironment. Oncogene. 2017;36:2191–201.PubMedCrossRef
3.
Aylett CH, Sauer E, Imseng S, Boehringer D, Hall MN, Ban N, et al. Architecture of human mTOR complex 1. Science. 2016;351:48–52.PubMedCrossRef
4.
5.
6.
Masri J, Bernath A, Martin J, Jo OD, Vartanian R, Funk A, et al. mTORC2 activity is elevated in gliomas and promotes growth and cell motility via overexpression of rictor. Cancer Res. 2007;67:11712–20.PubMedCrossRef
7.
8.
Hsieh AC, Costa M, Zollo O, Davis C, Feldman ME, Testa JR, et al. Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E. Cancer Cell. 2010;17:249–61.PubMedPubMedCentralCrossRef
9.
Nojima H, Tokunaga C, Eguchi S, Oshiro N, Hidayat S, Yoshino K, et al. The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. J Biol Chem. 2003;278:15461–4.PubMedCrossRef
10.
Hietakangas V, Cohen SM. TOR complex 2 is needed for cell cycle progression and anchorage-independent growth of MCF7 and PC3 tumor cells. BMC Cancer. 2008;8:282.PubMedPubMedCentralCrossRef
11.
12.
Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kappor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271–81.PubMedCrossRef
13.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.CrossRefPubMed
14.
Yamashita Y, Ikegami T, Suzuki M, Hirakawa H, Maeda H, Yamada S, et al. Hypopharyngeal cancer risk in Japanese: genetic polymorphisms related to the metabolism of alcohol- and tobacco-associated carcinogens. J Cancer Res Ther. 2019;15:556–63.PubMedCrossRef
15.
Yamashita Y, Ikegami T, Hirakawa H, Uehara T, Deng Z, Agena S, et al. Staging and prognosis of oropharyngeal carcinoma according to the 8th edition of the American joint committee on cancer staging manual in human papillomavirus infection. Eur Arch Otorhinolaryngol. 2019;276:827–36.PubMedCrossRef
16.
Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Xiao W, Kim E, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011;29:4294–301.PubMedPubMedCentralCrossRef
17.
Deng Z, Hasegawa M, Aoki K, Matayoshi S, Kiyuna A, Yamashita Y, et al. A comprehensive evaluation of human papillomavirus positive status and p16INK4a overexpression as a prognostic biomarker in head and neck squamous cell carcinoma. Int J Oncol. 2014;45:67–76.PubMedPubMedCentralCrossRef
18.
Ang KK, Sturgis EM. Human papillomavirus as a marker of the natural history and response to therapy of head and neck squamous cell carcinoma. Semin Radiat Oncol. 2012;22:128–42.PubMedCrossRef
19.
O'Sullivan B, Huang SH, Su J, Garden AS, Sturgis EM, Dahlstrom K, et al. Development and validation of a staging system for HPV-related oropharyngeal cancer by the international collaboration on Oropharyngeal cancer network for staging (ICON-S): a multicentre cohort study. Lancet Oncol. 2016;17:440–51.PubMedCrossRef
20.
Doescher J, Veit JA, Hoffmann TK. The 8th edition of the AJCC cancer staging manual : updates in otorhinolaryngology, head and neck surgery. HNO. 2017;65:956–61.PubMedCrossRef
21.
Orlandi E, Licitra L. Personalized medicine and the contradictions and limits of first-generation deescalation trials in patients with human papillomavirus-positive oropharyngeal cancer. JAMA Otolaryngol Head Neck Surg. 2018;144:99–100.PubMedCrossRef
22.
Masterson L, Moualed D, Liu ZW, Howard JE, Dwivedi RC, Tysome JR, et al. De-escalation treatment protocols for human papillomavirus-associated oropharyngeal squamous cell carcinoma: a systematic review and meta-analysis of current clinical trials. Eur J Cancer. 2014;50:2636–48.PubMedCrossRef
23.
Seiwert TY, Foster CC, Blair EA, Karrison TG, Agrawal N, Melotek JM, et al. OPTIMA: a phase II dose and volume de-escalation trial for human papillomavirus-positive oropharyngeal cancer. Ann Oncol. 2019;30:297–302.PubMedCrossRef
24.
Molinolo AA, Marsh C, El Dinali M, Gangane N, Jennison K, Hewitt S, et al. mTOR as a molecular target in HPV-associated oral and cervical squamous carcinomas. Clin Cancer Res. 2012;18:2558–68.PubMedPubMedCentralCrossRef
25.
26.
Spangle JM, Munger K. The human papillomavirus type 16 E6 oncoprotein activates mTORC1 signaling and increases protein synthesis. J Virol. 2010;84:9398–407.PubMedPubMedCentralCrossRef
27.
Simpson DR, Mell LK, Cohen EE. Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck. Oral Oncol. 2015;51:291–8.PubMedCrossRef
28.
Nguyen SA, Walker D, Gillespie MB, Gutkind JS, Day TA. mTOR inhibitors and its role in the treatment of head and neck squamous cell carcinoma. Curr Treat Options Oncol. 2012;13:71–81.PubMedCrossRef
29.
Coppock JD, Wieking BG, Molinolo AA, Gutkind JS, Miskimins WK, Lee JH. Improved clearance during treatment of HPV-positive head and neck cancer through mTOR inhibition. Neoplasia. 2013;15:620–30.PubMedPubMedCentralCrossRef
30.
Coppock JD, Lee JH. mTOR, metabolism, and the immune response in HPV-positive head and neck squamous cell cancer. World J Otorhinolaryngol Head Neck Surg. 2016;2:76–83.PubMedPubMedCentralCrossRef
31.
Bossler F, Hoppe-Seyler K, Hoppe-Seyler F. PI3K/AKT/mTOR signaling regulates the virus/host cell crosstalk in HPV-positive cervical cancer cells. Int J Mol Sci. 2019;20:2188.PubMedCentralCrossRef
32.
Grunwald V, Keilholz U, Boehm A, Guntinas-Lichius O, Hennemann B, Schmoll HJ, et al. TEMHEAD: a single-arm multicentre phase II study of temsirolimus in platin- and cetuximab refractory recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) of the German SCCHN group (AIO). Ann Oncol. 2015;26:561–7.PubMedCrossRef
33.
Ikegami T, Uehara T, Deng Z, Kondo S, Maeda H, Kiyuna A, et al. Detection of human papillomavirus in branchial cleft cysts. Oncol Lett. 2018;16:1571–8.PubMedPubMedCentral
34.
Mukhopadhyay S, Chatterjee A, Kogan D, Patel D, Foster DA. 5-Aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) enhances the efficacy of rapamycin in human cancer cells. Cell Cycle. 2015;14:3331–9.PubMedPubMedCentralCrossRef
35.
Yellen P, Saqcena M, Salloum D, Feng J, Preda A, Xu L, et al. High-dose rapamycin induces apoptosis in human cancer cells by dissociating mTOR complex 1 and suppressing phosphorylation of 4E-BP1. Cell Cycle. 2011;10:3948–56.PubMedPubMedCentralCrossRef
36.
Mukhopadhyay S, Saqcena M, Chatterjee A, Garcia A, Fias MA, Foster DA. Reciprocal regulation of AMP-activated protein kinase and phospholipase D. J Bio Chem. 2015;290:6986–93.CrossRef
37.
O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006;66:1500–8.PubMedPubMedCentralCrossRef
38.
Sun SY, Rosenberg LM, Wang X, Zhou Z, Yue P, Fu H, et al. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res. 2005;65:7052–8.PubMedCrossRef
39.
Dai Q, Xie F, Han Y, Ma X, Zhou S, Jiang L, et al. Inactivation of regulatory-associated protein of mTOR (raptor)/mammalian target of rapamycin complex 1 (mTORC1) signaling in osteoclasts increases bone mass by inhibiting osteoclast differentiation in mice. J Biol Chem. 2017;292:196–204.PubMedCrossRef
40.
Wu WK, Lee CW, Cho CH, Chan FK, Yu J, Sung JJ. RNA interference targeting raptor inhibits proliferation of gastric cancer cells. Exp Cell Res. 2011;317:1353–8.PubMedCrossRef
41.
Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366:520–9.PubMedCrossRef
42.
Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449–56.PubMedCrossRef
43.
Marques AE, Elias ST, Porporatti AL, Castilho RM, Squarize CH, De Luca CG, et al. mTOR pathway protein immunoexpression as a prognostic factor for survival in head and neck cancer patients: a systematic review and meta-analysis. J Oral Pathol Med. 2016;45:319–28.PubMedCrossRef
44.
Hara K, Mruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, et al. Raptor, binding rartner of target of rapamycin (TOR), mediates TOR action. Cell. 2002;110:117–89.CrossRef
45.
Elghazi L, Blandino-Rosano M, Alejandro E, Cras-Meneur C, Bernal-Mizrachi E. Role of nutrients and mTOR signaling in the regulation of pancreatic progenitors development. Mol Metab. 2017;6:560–73.PubMedPubMedCentralCrossRef
46.
Sun D, Liu H, Dai X, Zheng X, Yan J, Wei R, et al. Aspirin disrupts the mTOR-raptor complex and potentiates the anti-cancer activities of sorafenib via mTORC1 inhibition. Cancer Lett. 2017;406:105–15.PubMedCrossRef
47.
Koo J, Wang X, Owonikoko T, Ramalingam S, Khuri F, Sun S. GSK3 is required for rapalogs to induce degradation of some oncogenic proteins and to suppress cancer cell growth. Oncotarget. 2015;6:8974–87.PubMedPubMedCentralCrossRef
48.
Kaibori M, Shikata N, Sakaguchi T, Ishizaki M, Matsui K, Iida H, et al. Influence of Rictor and raptor expression of mTOR signaling on Long-term outcomes of patients with hepatocellular carcinoma. Dig Dis Sci. 2015;60:919–28.PubMedCrossRef
49.
Dunn LA, Fury MG, Xiao H, Baxi SS, Sherman EJ, Korte S, et al. A phase II study of temsirolimus added to low-dose weekly carboplatin and paclitaxel for patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Ann Oncol. 2017;28:2533–8.PubMedPubMedCentralCrossRef
50.
Ang KK, Harris J, Wheeler R, Weber R, DI R, Ngyen-Tan P, et al. Human papillomavirus and survival of pattents with oropharyngeal cancer. N Engl J Med. 2010;363:24–35.PubMedPubMedCentralCrossRef
51.
Deng Z, Hasegawa M, Yamashita Y, Matayoshi S, Kiyuna A, Agena S, et al. Prognostic value of human papillomavirus and squamous cell carcinoma antigen in head and neck squamous cell carcinoma. Cancer Sci. 2012;103:2127–34.PubMedPubMedCentralCrossRef
Metadata
Title
Raptor and rictor expression in patients with human papillomavirus-related oropharyngeal squamous cell carcinoma
Authors
Shunsuke Kondo
Hitoshi Hirakawa
Taro Ikegami
Takayuki Uehara
Shinya Agena
Jin Uezato
Hidetoshi Kinjyo
Noritomo Kise
Yukashi Yamashita
Katsunori Tanaka
Narumi Hasegawa
Asanori Kiyuna
Hiroyuki Maeda
Mikio Suzuki
Akira Gahana
Publication date
01-12-2021
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2021
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-021-07794-9

Other articles of this Issue 1/2021

BMC Cancer 1/2021 Go to the issue

Research

Aberrant overexpression of transcription factor Forkhead box D1 predicts poor prognosis and promotes cancer progression in HNSCC

Research article

A phase I study of the safety and activity of K-001 in patients with advanced pancreatic ductal adenocarcinoma

Research article

The impact of ICAM-1, CCL2 and TGM2 gene polymorphisms on differentiation syndrome in acute promyelocytic leukemia

Research article

Artificial intelligence for pre-operative lymph node staging in colorectal cancer: a systematic review and meta-analysis

Research article

Knockdown of circ_0011946 targets miR-216a-5p/BCL2L2 axis to regulate proliferation, migration, invasion and apoptosis of oral squamous cell carcinoma cells

Research article

MiR-3168, miR-6125, and miR-4718 as potential predictors of cisplatin-induced nephrotoxicity in patients with head and neck cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits