Only the CCND1-CDK4 and CDK6 complex has raised interest as a possible actionable target, whereas, in contrast, despite its prognostic relevance in cancer [76], the regulatory member CCND1 per se has received less attention. As previously quoted, palpociclib induces autophagy in cancer, targeting CDK4 and CDK6 [54,55], via the LKB1 and Ser325 phosphorylation resulting in a CCND1-mediated, reduced activation of AMPK [77]. The CCND1 gene encoding CCND1 is activated in B-cell lymphomas and overexpressed in many other human cancers (esophageal, lung, breast, bladder carcinomas, etc.) where it acts as a proto-oncogene. Therefore, the CCND1 is a potential pivotal actionable target for cell cycle arrest. In normal cells, CCND1 has a very short life due to UPS degradation whereas in cancer cells, inhibition of turnover and increased levels of CCND1 were shown. Conversely, the knockdown of the activity of a specific deubiquitinase for CCND1 was shown, inducing growth suppression in cancer cells addicted to its expression [78]. Ubiquitination of CCND1 is achievable in response to IR [79] and, in cancer cells, IR or other DNA-damaging agents may activate selective autophagy [54]. Autophagy shares common molecular mechanisms with UPS, with which it is intertwined in a close and complex relationship [80]. As described by these authors, ubiquitin-specific recognition can have a pivotal role for CCND1 autophagy degradation. Selective autophagy requires some receptor proteins necessary for the process, such as p62 (also known as sequestosome 1 or SQSTM1), NBR1 (neighbor of the BRCA 1 gene), CALCOCO2 (calcium binding and coiled-coil domain 2), and optineurin. p62 (the most relevant receptor protein for the subject dealt with here) is a component of several transduction signal cascades, such as Keap-Nrf2, and essential for UPS degradation.

Possible future strategies aimed at enhancing the IR-autophagic degradation of CCND1 in combination with drugs targeting the CCND1-CDK4 and CDK6 complex for G1/S arrest could overcome the IR-resistance of G1 and S phases of cell cycle

Ionizing radiation can directly induce autophagy; although the mechanism underlying this effect has not been fully elucidated so far, two main mechanisms have been evoked: (1) similarly to rapamycin, IR reverts auto-phosphorylation of mTOR (e.g., in MCF-7 breast cancer cell culture) leading to the formation of autophagic vacuoles, segregation of cytoplasmic materials, and appearance of LC3 positivity and eventually mitochondrial hyperpolarization and decreased cell survival [81].

(2) Radiation causes a protective pathway via endoplasmic reticulum (ER) stress, accumulation of ER misfolded proteins (unfolded protein response—UPR), and autophagy. Therefore, UPR pathway and autophagy are upregulated in some cancer types as an escape strategy leading to IR-activated autophagy responsible for resistance to RT [82,83,84]. Nonetheless, autophagy is always depictable as a “double-edged sword”. As previously reviewed [80], most of the literature dedicated to this subject is focused on drug manipulation of autophagy (i.e., either induction or inhibition) for improving IR-sensitivity in cancer cells, more than to IR in conditioning, per se, autophagy towards cell death.

Emphasis should be placed in autophagy during the cell cycle, as different studies have investigated the autophagy activation in the different phases of the cell cycle [81,82]. In contrast, other evidence suggests a protective suppression of autophagy during mitosis aimed at preventing the inappropriate inactivation of molecular species and organelles, functional for cellular replication, or even aggregated chromosomes [50]. IR-based autophagy induced during the G1 and S counteracts the accelerated cell cycle in cancer and lays the groundwork for combined therapies combined with IR. It has been shown that CCND1 suppresses autophagy in mammary epithelium [85] whereas CCND1 inhibits autophagy by activating AMPK in breast cancer cells [77]. Further, in 2016, our group published a study in recurrent GB patients that prompted us to hypothesize a role for the IR-temozolomide treatment in inducing CCND1 autophagic degradation in Beclin-1-positive GBs [59]. Consistently, another group demonstrated the inverse correlation between low autophagic activity and high CCND1 expression that were also related to poorer prognosis [4]. In human and murine models of hepatocellular carcinomas (HCC), induction of autophagy led to CCND1 ubiquitination and its recruitment into autophagosomes via SQSTM1, formation of autophago-lysosomes, and degradation with suppression of tumor growth. Further, Chen et al. in 2019 [58] showed that autophagy itself causes CCND1 autophagic degradation in breast cancer cell lines with subsequent G1 cell cycle arrest underpinning the hypothesis of cell cycle modulation by CCND1 via mTORC1 signaling inhibition. Finally, we proposed in 2020 an overview of the role of autophagy, and namely its pivotal Beclin-1 protein, in CCND1 degradation, as a possibly actionable mechanism for G1/S cell cycle arrest in cancer (Figure 3) [86].

It is still unclear whether autophagy could represent a true per se pro-death process, or can simply enhance the IR and chemotherapy sensitivity of cancer cells. The impact of autophagy in a cell death progress is cautiously named “autophagy-related cell death”. This definition is underpinned by the clinical observation that a high tissue expression of cytoplasmic Beclin-1 was related to better prognosis in patients with malignant glioma on temozolomide chemotherapy and radiotherapy [87]. Notwithstanding, one should also take account of the tumor suppression of the autophagy-independent functions of Beclin-1 [88].