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Targeting Autophagy in Thyroid Cancers

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Targeting Autophagy in Thyroid Cancers 26 4 Endocrine-Related W Wei et al. Autophagy in thyroid cancers 26:4 R181–R194 Cancer REVIEW Targeting autophagy in thyroid cancers Weijun Wei1,2, Heather Hardin3 and Quan-Yong Luo1 1Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China 2Shanghai Jiao Tong University School of Medicine, Shanghai, China 3Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA Correspondence should be addressed to Q-Y Luo: [email protected] Abstract Thyroid cancer is one of the most common endocrine malignancies. Although Key Words the prognosis for the majority of thyroid cancers is relatively good, patients with f thyroid cancer metastatic, radioiodine-refractory or anaplastic thyroid cancers have an unfavorable f autophagy outcome. With the gradual understanding of the oncogenic events in thyroid cancers, f radioiodine molecularly targeted therapy using tyrosine kinase inhibitors (TKIs) is greatly changing f molecularly targeted the therapeutic landscape of radioiodine-refractory differentiated thyroid cancers therapy (RR-DTCs), but intrinsic and acquired drug resistance, as well as adverse effects, may f RR-DTC limit their clinical efficacy and use. In this setting, development of synergistic treatment options is of clinical significance, which may enhance the therapeutic effect of current TKIs and further overcome the resultant drug resistance. Autophagy is a critical cellular process involved not only in protecting cells and organisms from stressors but also in the maintenance and development of various kinds of cancers. Substantial studies have explored the complex role of autophagy in thyroid cancers. Specifically, autophagy plays important roles in mediating the drug resistance of small-molecular therapeutics, in regulating the dedifferentiation process of thyroid cancers and also in affecting the treatment outcome of radioiodine therapy. Exploring how autophagy intertwines in the development and dedifferentiation process of thyroid cancers is essential, which will enable a more profound understanding of the physiopathology of thyroid cancers. More importantly, these advances may fuel future development of autophagy-targeted therapeutic strategies for patients with thyroid cancers. Herein, we summarize the most recent evidence uncovering the role of autophagy in thyroid cancers and highlight future research perspectives in this regard. Endocrine-Related Cancer (2019) 26, R181–R194 Introduction Thyroid cancer is the fifth most common cancer in women cancer (ATC) and medullary thyroid cancer (MTC)). in the United States and is the most commonly diagnosed DTC accounts for more than 95% of thyroid cancers and cancer before the age of 30 years among women in China contains two major subtypes (i.e., papillary thyroid cancer (Chen et al. 2016). Although thyroid cancer is generally (PTC) and follicular thyroid cancer (FTC)). While patients considered as an indolent tumor, it has a broad range with lower risk diseases or benign thyroid nodules should of clinical behaviors ranging from an indolent tumor not be overtreated, those with advanced diseases should under the umbrella term of differentiated thyroid cancer be given more aggressive and efficacious treatments. (DTC) to more aggressive types (i.e., anaplastic thyroid Currently, a combination of surgery, radioactive iodine https://erc.bioscientifica.com © 2019 Society for Endocrinology https://doi.org/10.1530/ERC-18-0502 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 10/01/2021 06:44:14PM via free access -18-0502 Endocrine-Related W Wei et al. Autophagy in thyroid cancers 26:4 R182 Cancer (RAI, 131I) and subsequent TSH suppression therapy is occurs in up to 50% of PTCs and 45% of ATCs (Xing 2013, the mainstay of therapy for most DTC patients (Wei et al. Landa et al. 2016, Molinaro et al. 2017, Sandulache et al. 2018b). However, due to tumor dedifferentiation and 2017). As such, molecularly targeted therapy suppressing concomitant loss of sodium/iodide symporter (NIS), oncogenic proteins like BRAFV600E has increasingly been certain thyroid cancer patients are insensitive or resistant used for patients with radioiodine-refractory differentiated to RAI therapy (Song et al. 2015). Although rare, ATC is the thyroid cancer (RR-DTC). Currently, vemurafenib and most aggressive form of thyroid cancers and is a clinical dabrafenib are two selective BRAFV600E inhibitors under challenge owing to its pleomorphic histopathological clinical investigation for DTC patients harboring BRAFV600E features and rapid progression (Ragazzi et al. 2014, mutation. In addition, two multi-kinase inhibitors with Keutgen et al. 2015, Tiedje et al. 2018). antiangiogenic properties, sorafenib and lenvatinib, have The MAPK oncogenic pathway is closely involved in been licensed for treating RR-DTC and showed advantages the proliferation, invasion and differentiation status of in terms of progression-free survival. However, drug thyroid cancers (Fig. 1; Xing 2013). BRAF (v-raf murine resistance and adverse effects associated with the single- sarcoma viral oncogene homolog B) is one of the well- agent treatment often lead to termination of the targeted characterized members of the MAPK pathway and therapy (Shen et al. 2014). Furthermore, the impact of somatic BRAF mutation, especially BRAFV600E mutation, these TKIs on overall survival of patients with RR-DTC Figure 1 The MAPK and PI3K oncogenic signaling pathways are the main signaling cascades implicated in the thyroid cancer initiation, progression and dedifferentiation. The genetic mutation in theBRAF gene most commonly results in amino acid transformation at the 600 locus in the BRAF protein. The mutated BRAF (i.e., BRAFV600E) has enzymatic function and transmits messages by phosphorylating downstream protein MEK. BRAFV600E mutation in the thyroid may lead to significant reduction of proteins responsible for radioiodine uptake in both mouse models and in humans. Inhibitors blocking either mutated BRAF and/or MEK restore RAI uptake and prolong retention of radioiodine in the thyroid cancer cells. In addition to the MAPK signaling cascade, the PI3K pathway is also involved in the initiation and progression of thyroid cancers. PTEN switches off PI3K signaling by dephosphorylating PIP3 and therefore is a tumor suppressor. ALK, anaplastic lymphoma kinase; BRAF, rapidly accelerated fibrosarcoma type-B or v-raf murine sarcoma viral oncogene homolog B; MAPK, mitogen-activated protein kinase; NTRK, neurotrophic receptor tyrosine kinase; PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate; PTEN, phosphatase and tensin homolog deleted on chromosome 10; RAS, rat sarcoma; RET, rearranged during transfection; RTK, receptor tyrosine kinase. A full color version of this figure is available athttps://doi.org/10.1530/ERC-18-0502 . https://erc.bioscientifica.com © 2019 Society for Endocrinology https://doi.org/10.1530/ERC-18-0502 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 10/01/2021 06:44:14PM via free access Endocrine-Related W Wei et al. Autophagy in thyroid cancers 26:4 R183 Cancer has not been proven yet. Meanwhile, redifferentiation of cancers may directly or indirectly regulate the activity RR-DTC emerges as a very promising approach to restore of autophagy in thyroid cancers. Additionally, somatic NIS expression and to enable 131I therapy (Ho et al. 2013, mutations/deletions of mitochondrial DNA and alteration Rothenberg et al. 2015, Dunn et al. 2018). Nonetheless, of mitochondrial biogenesis are associated with the novel strategies that can enhance the efficacy of TKIs carcinogenesis of a portion of Hürthle cell tumors, which and/or overcome resistance of TKIs are in urgent need to are characterized by the cytoplasmic accumulation of refine the clinical management of RR-DTCs and ATCs. abundant mitochondria (Maximo et al. 2012). As a specific Macroautophagy (hereafter referred to as autophagy) type of autophagy dealing with redundant mitochondria is a process that captures and degrades intracellular (Youle & Narendra 2011), mitophagy plays an important components in lysosomes, thereby sustaining metabolic role in the evolution of Hürthle cell tumors (Yi et al. 2017). homeostasis and promoting the growth of a broad PTEN (phosphatase and tensin homolog deleted on spectrum of cancers under certain conditions. Autophagy chromosome 10) is a tumor suppressor but its function is not only occurs upon nutrient deprivation to supply disabled in several human cancers. Although endogenous cells with building blocks but also occurs under nutrient- expression of HRASG12V alone is insufficient to drive rich conditions to mediate the removal of superfluous or thyroid tumorigenesis (Chen et al. 2009), and thyroid- damaged organelles and potentially toxic protein aggregates specific knock-in of BRAFV600E induces mostly benign (White et al. 2015, Klionsky et al. 2016). Mitophagy is a lesions (Franco et al. 2011), loss of p53 or concomitant selective form of autophagy that mediates the removal of loss of function of PTEN and p53 could induce initiation mitochondria. Loss of mitochondrial membrane potential and progression of ATC (Antico Arciuch et al. 2011, (ΔΨm) and mitochondrial fragmentation generally precede McFadden et al. 2014). In addition, PTEN is a critical mitophagy (Youle
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