IGF1 receptor inhibition amplifies the effects of cancer drugs by autophagy and immune-dependent mechanisms

Wu, Qi; Tian, Ai-Ling; Li, Bei; Leduc, Marion; Forveille, Sabrina; Hamley, Peter; Galloway, Warren R. J. D.; Xie, Wei; Liu, Peng; Zhao, Lu; Zhang, Shuai; Hui, Pei; Madeo, Frank; Tu, Yi; Kepp, Oliver; Kroemer, Guido

doi:10.1136/jitc-2021-002722

Cited by 50 publications

(31 citation statements)

References 63 publications

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“…IGF1R can inhibit AMPK activity via Akt1, which phosphorylates an AMPK inhibitory site [ 54 ] ( Figure 8 ). Picropodophyllin has been recently discovered as a potent inducer of autophagic flux that acts on-target [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

Survival of HT29 Cancer Cells Is Affected by IGF1R Inhibition via Modulation of Self-DNA-Triggered TLR9 Signaling and the Autophagy Response

Sípos¹,

Barta²,

Simon³

et al. 2022

Pathol. Oncol. Res.

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Purpose: In HT29 colon cancer cells, a close interplay between self-DNA-induced TLR9 signaling and autophagy response was found, with remarkable effects on cell survival and differentiation. IGF1R activation drives the development and malignant progression of colorectal cancer. IGF1R inhibition displays a controversial effect on autophagy. The interrelated roles of IGF1R inhibition and TLR9/autophagy signaling in HT29 cancer cells have not yet been clarified. In our study, we aimed to investigate the complex interplay of IGF1R inhibition and TLR9/autophagy signaling in HT29 cells.Methods: HT29 cells were incubated with tumor-originated self-DNA with or without inhibitors of IGF1R (picropodophyllin), autophagy (chloroquine), and TLR9 (ODN2088), respectively. Cell proliferation and metabolic activity measurements, direct cell counting, NanoString and Taqman gene expression analyses, immunocytochemistry, WES Simple Western blot, and transmission electron microscopy investigations were performed.Results: The concomitant use of tumor-derived self-DNA and IGF1R inhibitors displays anti-proliferative potential, which can be reversed by parallel TLR9 signaling inhibition. The distinct effects of picropodophyllin, ODN2088, and chloroquine per se or in combination on HT29 cell proliferation and autophagy suggest that either the IGF1R-associated or non-associated autophagy machinery is “Janus-faced” regarding its actions on cell proliferation. Autophagy, induced by different combinations of self-DNA and inhibitors is not sufficient to rescue HT29 cells from death but results in the survival of some CD133-positive stem-like HT29 cells.Conclusion: The creation of new types of combined IGF1R, autophagy, and/or TLR9 signaling inhibitors would play a significant role in the development of more personalized anti-tumor therapies for colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

Survival of HT29 Cancer Cells Is Affected by IGF1R Inhibition via Modulation of Self-DNA-Triggered TLR9 Signaling and the Autophagy Response

Sípos¹,

Barta²,

Simon³

et al. 2022

Pathol. Oncol. Res.

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“…There have been some evidence that targeting the IGF1 pathway may be effective in controlling a variety of cancers. An IGF1 inhibitor could strongly control cell growth of ER positive breast cancer cells 30 .Targeting IGF1R ampli es the effects of chemotherapy via autophagy and immune-dependent mechanisms in triple-negative breast cancer 31 . Some researchers have developed IGF1R targeted theranostic nanoparticles for precision therapy of pancreatic cancer 32 .However, there is still a lack of relevant researches in OC, especially in OCCC.…”

Section: Discussionmentioning

confidence: 99%

OSI-906 restores the sensitivity of ovarian clear cell carcinoma to cisplatin by targeting the IGF1R/AKT pathway

et al. 2022

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Among the various histologic subtypes of ovarian cancers (OCs), ovarian clear cell carcinoma (OCCC) represents a great challenge due to its disease aggressiveness and resistance to chemotherapy. IGF1 is overexpressed in epithelial ovarian cancer (EOC), and IGF1 pathway activation is related to the chemoresistance of various cancers. In this study, we found that the expression level of IGF1 was higher in OCCC than in the most common type of OC, high-grade serous adenocarcinoma (HGSC). Then, we investigated the role of IGF1 pathway activation in the progression of OCCC, observing that activation of the IGF1 pathway using IGF1 promoted the proliferation and migration of ES2 cells, while inactivation of the IGF1 pathway using the selective IGF1R inhibitor OSI-906 reversed the alteration mediated by IGF1.Based on the role of the IGF1 pathway in cancer chemoresistance, we proposed that OSI-906 may restore the sensitivity of OCCC to cisplatin. We rst validated that IGF1 increased the IC50 value of cisplatin in ES2 cells, while OSI-906 decreased it. Then we con rmed that IGF1 decreased the apoptosis rate of ES2 cells induced by cisplatin, while OSI-906 increased it. Finally, we conducted animal experiments to investigate whether OSI-906 helps cisplatin control the growth of OCCC. As expected, OSI-906 increased the effect of cisplatin in attenuating the growth of OCCC in vivo. Therefore, we conclude that using OSI-906 may be an effective method to restore the sensitivity of OCCC to cisplatin by targeting the IGF1R/AKT pathway.

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“…Guido Kroemer, Université de Paris, France, pointed out that caloric restriction mimetics enhances autophagy which improves longevity. Additionally, caloric restriction mimetics can be used in the treatment of diseases such as cancer; here the Kroemer group showed that the IGF1R inhibitor picropodophyllin enhance the efficacy of chemoimmunotherapy by stimulating immunosurveillance in mice [24,25]. Valter Longo, USC Davis School of Gerontology, USA, discussed fasting mimicking diets in relation to vitamin C treatment of cancer cells.…”

Section: The Benefits Of Dietary Restrictionmentioning

confidence: 99%

Meeting Report: Aging Research and Drug Discovery

Meron

Thaysen

Angeli

et al. 2022

Aging

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Aging is the single largest risk factor for most chronic diseases, and thus possesses large socioeconomic interest to continuously aging societies. Consequently, the field of aging research is expanding alongside a growing focus from the industry and investors in aging research. This year's 8th Annual Aging Research and Drug Discovery (ARDD) meeting was organized as a hybrid meeting from August 30th to September 3rd 2021 with more than 130 attendees participating on-site at the Ceremonial Hall at University of Copenhagen, Denmark, and 1800 engaging online. The conference comprised of presentations from 75 speakers focusing on new research in topics including mechanisms of aging and how these can be modulated as well as the use of AI and new standards of practices within aging research. This year, a longevity workshop was included to build stronger connections with the clinical community.

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IGF1 receptor inhibition amplifies the effects of cancer drugs by autophagy and immune-dependent mechanisms

Cited by 50 publications

References 63 publications

Survival of HT29 Cancer Cells Is Affected by IGF1R Inhibition via Modulation of Self-DNA-Triggered TLR9 Signaling and the Autophagy Response

Survival of HT29 Cancer Cells Is Affected by IGF1R Inhibition via Modulation of Self-DNA-Triggered TLR9 Signaling and the Autophagy Response

OSI-906 restores the sensitivity of ovarian clear cell carcinoma to cisplatin by targeting the IGF1R/AKT pathway

Meeting Report: Aging Research and Drug Discovery

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