Combined inhibition of atypical PKC and histone deacetylase 1 is cooperative in basal cell carcinoma treatment

Mirza, Asra; Fry, M.; Urman, Nicole M.; Atwood, Scott X.; Roffey, Jon; Ott, Gregory R.; Chen, Bin; Lee, Alexander; Brown, Allan H.; Aasi, Sumaira Z.; Hollmig, Tyler; Ator, Mark A.; Dorsey, Bruce D.; Ruggeri, Bruce; Zificsak, Craig A.; Sirota, Marina; Tang, Jean Y.; Butte, Atul J.; Epstein, Ervin; Sarin, Kavita Y.; Oro, Anthony E.

doi:10.1172/jci.insight.97071

Cited by 50 publications

(36 citation statements)

References 26 publications

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“…Activation of PKC signaling is involved in the development of multidrug resistance (MDR) phenotype by phosphorylation of p-glycoprotein in cancer cells (Rumsby et al, 1998). On the other hand, inhibition of atypical PKC has improved clinical outcomes in advanced basal cell carcinoma (BCCs) (Mirza et al, 2017). Therefore, IFIT2 depletion may promote drug resistance.…”

Section: Ifits In Drug Resistancementioning

confidence: 99%

Emerging Functions of Human IFIT Proteins in Cancer

Pidugu

et al. 2019

Front. Mol. Biosci.

104

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Interferon-induced protein with tetratricopeptide repeats (IFIT) genes are prominent interferon-stimulated genes (ISGs). The human IFIT gene family consists of four genes named IFIT1, IFIT2, IFIT3, and IFIT5. The expression of IFIT genes is very low in most cell types, whereas their expression is greatly enhanced by interferon treatment, viral infection, and pathogen-associated molecular patterns (PAMPs). The proteins encoded by IFIT genes have multiple tetratricopeptide repeat (TPR) motifs. IFIT proteins do not have any known enzymatic roles. However, they execute a variety of cellular functions by mediating protein-protein interactions and forming multiprotein complexes with cellular and viral proteins through their multiple TPR motifs. The versatile tertiary structure of TPR motifs in IFIT proteins enables them to be involved in distinct biological functions, including host innate immunity, antiviral immune response, virus-induced translation initiation, replication, double-stranded RNA signaling, and PAMP recognition. The current understanding of the IFIT proteins and their role in cellular signaling mechanisms is limited to the antiviral immune response and innate immunity. However, recent studies on IFIT protein functions and their involvement in various molecular signaling mechanisms have implicated them in cancer progression and metastasis. In this article, we focused on critical molecular, biological and oncogenic functions of human IFIT proteins by reviewing their prognostic significance in health and cancer. Research suggests that IFIT proteins could be novel therapeutic targets for cancer therapy.

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Section: Ifits In Drug Resistancementioning

confidence: 99%

Emerging Functions of Human IFIT Proteins in Cancer

Pidugu

et al. 2019

Front. Mol. Biosci.

104

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“…Resistance to SMO inhibitors primarily occurs through secondary mutations in SMO that either prevent drug binding or result in constitutive activation even when drug is bound [10,11] . Recent work on circumventing SMO inhibition has concentrated on shutting down GLI activation, where preclinical targeting of aPKC [10,12] , HDAC1 [13,14] , MKL1 [15] , and MEKK2/3 [16] have all shown some efficacy.…”

Section: Introductionmentioning

confidence: 99%

MTOR promotes basal cell carcinoma growth through atypical PKC

Chow

Levee

Kaur

et al. 2020

Preprint

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Advanced basal cell carcinomas (BCCs) are driven by the Hedgehog (HH) pathway and often possess inherent resistance to SMO inhibitors. Identifying and targeting pathways that bypass SMO could provide alternative treatments for patients with advanced or metastatic BCC. Here, we use a combination of RNA-sequencing analysis of advanced human BCC tumor-normal pairs and immunostaining of human and mouse BCC samples to identify an MTOR expression signature in BCC. Pharmacological inhibition of MTOR activity in BCC cells significantly reduces cell proliferation without affecting HH signaling. Similarly, treatment of the Ptch1fl/fl; Gli1-CreERT2 mouse BCC tumor model with everolimus reduces tumor growth. aPKC, a downstream target of MTOR, shows reduced activity, suggesting that MTOR promotes tumor growth by activating aPKC and demonstrating that suppressing MTOR could be a promising target for BCC patients.

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“…Another aPKC inhibitor, CRT0066854-a thienol[2,3-d]pyrimidine-based compound, has approximately five-fold selectivity for PRKCI over PRKCZ [70]. A structure-based azaquinazoline derivative of CRT0066854, CRT0329868, shows greater than 10-fold increased IC 50 (inhibitory concentration 50 or the concentration of the inhibitor at which kinase activity is diminished by 50%) for PRKCI, favorable pharmacokinetic properties and excellent oral bioavailability [71]. A distinct class of aPKC inhibitors include the PIF-pocket targeted allosteric inhibitors.…”

Section: Apkc Inhibitorsmentioning

confidence: 99%

aPKC in neuronal differentiation, maturation and function

2019

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The atypical Protein Kinase Cs (aPKCs)—PRKCI, PRKCZ and PKMζ—form a subfamily within the Protein Kinase C (PKC) family. These kinases are expressed in the nervous system, including during its development and in adulthood. One of the aPKCs, PKMζ, appears to be restricted to the nervous system. aPKCs are known to play a role in a variety of cellular responses such as proliferation, differentiation, polarity, migration, survival and key metabolic functions such as glucose uptake, that are critical for nervous system development and function. Therefore, these kinases have garnered a lot of interest in terms of their functional role in the nervous system. Here we review the expression and function of aPKCs in neural development and in neuronal maturation and function. Despite seemingly paradoxical findings with genetic deletion versus gene silencing approaches, we posit that aPKCs are likely candidates for regulating many important neurodevelopmental and neuronal functions, and may be associated with a number of human neuropsychiatric diseases.

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Combined inhibition of atypical PKC and histone deacetylase 1 is cooperative in basal cell carcinoma treatment

Cited by 50 publications

References 26 publications

Emerging Functions of Human IFIT Proteins in Cancer

Emerging Functions of Human IFIT Proteins in Cancer

MTOR promotes basal cell carcinoma growth through atypical PKC

aPKC in neuronal differentiation, maturation and function

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